Taxanes: This class of drugs includes Taxotere, Taxol, and protein-bound Abraxane. â¢. Cytoxan. â¢. Xeloda and 5 fluorouracil (5 FU). â¢. Navelbine. â¢. Gemzar.
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Theivendren Panneer Selvam Apeksha Phatde
Evaluation of Thiazole Heterocycles against Cancer – A Review
Dr. T. PanneerSelvam M.Pharm., Ph.D Is working as an Associate Professor in Arulmigu Kalasalingam College of Pharmacy, Krishnankoil, Tamilnadu. He received his PhD degree in 2013 from Acharya Nagarjuna University, Guntur, India and he earned Young Faculty Award 2014 from EET CRS presents Academic Brilliance Award-2014, Noida and has 08 years of teaching experience, scientific research and development. He has published 20 Books, 50 scientific research and 02 review articles in international and national journals. His research
has
focused
Analytical/Biological Derivatives.
on
the
Screening
Design, of
Synthesis,
Novel
and
Heterocyclic
Apeksha Phatde B.Pharm., Is currently a research student’s pursuing his master’s degree in the field of Pharmaceutical Chemistry at P.E.S’s Rajaram and Tarabai Bandekar College of Pharmacy at Ponda in Goa. Her area of research has focused on the Design, Synthesis, and Analytical/Biological Screening of Novel Heterocyclic Derivatives.
ABSTRACT Cancer is one of the leading causes of death in people. People from any age group may get cancer. Cancer is not usually detected in early stages, so awareness should be created among all the age groups about the early cancer signs and symptoms as identifying and diagnosing them would save a life. The aim of the present work is, researcher should know all the basic information about the various treatments available for treating cancer as well as importance of thiazole nucleus.
Index Content Introduction Reference Review of literature Reference Conclusion
Page Number 1-31 32 34-88 89-100 101
INTRODUCTION: The anticancer drugs are most toxic drugs used in the therapy. These drugs either kill cancer cells or modify their growth. Cancer chemotherapy is nowadays established and has a great value. Drugs are also used in conjunction with radiotherapy, surgery and immunotherapy. When cancer spreads it is much harder to treat. Abnormal cells divide rapidly and form tumours. Cancer is defined as an uncontrolled growth of abnormal cells. Treatment with drugs started after 1940 when nitrogen mustard was used, but rapid progress has been observed. Attempts have been made to define optimal combinations, strategies for treatments
and
measures
for
patients
support.
Cancer
chemotherapy is nowadays established and has a great value. Drugs are also used in conjunction with radiotherapy, surgery and immunotherapy. Cancer is one of the leading causes of death in people. People from any age group may get cancer. Cancer is not usually detected in early stages, so awareness should be created among all the age groups about the early cancer signs and symptoms as identifying and diagnosing them would save a life. The aim of the present work is, researcher should know all the basic information about the various treatments available for treating cancer as well as importance of thiazole nucleus. Thiazole and its derivatives are well-known as sulphur & nitrogen heterocycles. Thiazole and its derivatives are the most active classes of compounds, which possess wide range of 1
biological activities like anti-bacterial, anticonvulsant, analgesic, antimicrobial,
antiinflammatory,
antidiabetic,
sedative
antirheumatic, anticancer, and antitubercular activities. Majority of cytotoxic drugs have more profound effect on rapidly multiplying cells because the most important targeted site of action is the nucleic acids and their precursors. The thiazole nucleus is important in the field of pharmacy as well as to develop newer anticancer agent. It is used to emphasize various synthetic molecules to promote the pyrazole molecule as anticancer agent. CLASSIFICATION OF CANCER: • Adenomas: cancers of thyroid, pituitary gland, adrenal
gland and other glandular tissues. • Lymphomas: cancers that begin in the immune system
tissues and the lymph nodes. • Leukaemia’s: cancers which begin in the blood stream
and accumulate in the bloodstream. • Sarcomas:
sarcomas are characterised by that are
situated in bone, fat, cartilage, connective tissue, muscle and other supportive tissues. • Carcinomas: characterised by cells that cover internal and
externals parts of the body like lung, breast and colon cancer. HISTORY OF CANCER: Cancer is not only seen in human beings but also other animals and has been recorded throughout the history. Now cancer is one of the leading causes of death. Today, millions of people 2
extend their life due to a number of treatment methods available. Hippocrates (460-370 BC) used the Greek word karkinos to describe carcinoma tumours hence, the word cancer, but he’s not the first to discover it. Evidences have been found from fossilized bones and human mummies. Oldest description of cancer was found in 3000 BC that was discovered in Egypt which is called the Edwin Smith Papyrus and is a part of ancient Egyptian textbook on trauma surgery. The Greek term was translated into cancer, which is the Latin term for crab by the Roman physician, Celsus (28-50 BC). Galen (130-200 AD), Greek physician used the word oncos to describe swelling in tumour and hence today the cancer specialists are known as oncologists. Physicians did not know the exact cause of cancer in the earliest times hence many physicians described different theories about the cause of cancer. Humoral theory: Hippocrates believed that a human body was made up of four humors i.e. body fluids (blood, phlegm, yellow bile and black bile) and when these humors were balanced the person remained healthy. Any change in these humors could lead to disease. Too much of black bile in various body sites was thought to cause cancer. This theory was followed for over 1300 years.
3
Lymph theory: In this theory it was suggested that cancer was formed by another body fluid, lymph. Human body was made up of solid parts through which there is continuous movement of the fluids. Stahl and Hoffman theorized that cancer was formed by fermenting and degenerating lymph varying in density, acidity and alkalinity. Balstema theory: German pathologist Johannes Muller in 1838 showed that cancer is made up of cells and not lymph and believed that these cancer cells did not come from normal cells. Chronic irritation theory: Virchow suggested that the cause of cancer was chronic irritation, but he falsely believed that cancers spread like a liquid. Karl Thiersch a German surgeon in 1860s showed that cancers metastasize through the spread of malignant cells and not through body fluids. Trauma theory: From 1800s until 1920s trauma was thought to cause cancers despite the advances in understanding cancer. Infectious disease theory: Two doctors in Holland reported that cancer is contagious and suggested that cancer patients should be isolated. Because it was believed that cancer was contagious the first hospital in 1779 for cancer in France was away from the city.
4
CANCER STATUS: The most common cancers have been changing from past 40 years. Most common cancers since 1975 are lung, breast, colorectal, stomach and prostate cancers. Lung cancer and prostate cancer are more common in men while breast cancer is very common in females. Worldwide statistics suggests that there were around 32.5 million men and women still alive in 2012, after up to 5 years of diagnosis and majority of them were diagnosed with breast cancer and lung cancer. In India, cancer is the second common disease responsible for mortality of people which is about 0.3 million people every year. All the types of cancers are reported in India out of which breast cancer is very common among the females while oral cancer among males. Types of cancers •
Adrenal cancer
•
Anal cancer
•
Bile duct cancer
•
Bladder cancer
•
Bone cancer
•
Brain cancer
•
Breast cancer
•
Cervical cancer
•
Colorectal cancer
•
Endometrium cancer
•
Oesophagus cancer
•
Eye cancer 5
•
Gallbladder cancer
•
Kidney cancer
•
Leukaemia
•
Liver cancer
•
Lung cancer
•
Para nasal sinus cancer
•
Nasopharyngeal cancer
•
Oral cavity cancer
•
Ovarian cancer
•
Pancreatic cancer
•
Penile cancer
•
Prostate cancer
•
Salivary gland cancer
•
Skin cancer
•
Small intestine cancer
•
Testicular cancer
•
Thymus cancer
•
Thyroid cancer
•
Vaginal cancer
6
Various cell lines for different cancers: Cancerous part
Cancer cell lines
Lung cancer
NCI-H125, -H125, -H226, -H358, -H661, MTT, GLC-2, GLC-4, GLC-36 A549, Y-90, SPC-A1, H460, H322, H187, N417
Breast cancer
MCF-7, MDA-MB-435, B-Cap37
Prostate cancer
PC-3, DU 145 , CaP, LN CaP LN 3, BT474, C4-2
Bladder cancer
K9TCC-PU-AxA, K9TCC-PU-AxC
Pancreatic
SW-1990, PK1, AsPC1, CfPAC1,
cancer
CAPAN-2
Ovarian cancer
OV-1063, OAW28, OAW41M, OAW42, OAW59M, 0138B, 0108D, 0253D, HO-8910
Colorectal
LoVo
cancer Colon cancer
HT 29mdr
Liver cancer
BEL-7402, KIM-1, KYN-1, KYN-2, KYN-3, HAK-6, HAK-5, HAK-4
Cervical cancer
HeLa
Gastric cancer
MKN-45, KATOIII
Epithelial
A431
carcinoma Salivary cancer
HSGAZA3
7
Larynx cancer
Vero, Hep-2
Oral squamous
HSC-3, HSC-4, Ca9-22, Ho-1-U-1,
cell carcinoma
Ho-1 N-1 AND KB
Human
HL-60
promyelocytic Leukemia Colorectal
Colo-205
adenocarcinoma Skin fibroblast
NF-103
cells Brain
SF295
Kidney cancer
HEK 293
8
TREATMENTS USED FOR CANCER: There is no one single treatment used for cancer, a combination of therapies are used. Type of treatment depends on various factors which include age and health of the person, type of cancer and how much it has spread. Treatment for cancer fall into one of the following categories: surgery, radiation, chemotherapy, immunotherapy, hormone therapy or gene therapy. Surgery Surgery is one of the oldest methods used to remove the cancer. Surgery can be used to remove the cancer if it has not spread which is possible only if the cancer is detected in early stages. Surgery is mostly carried out in patients with breast cancer, prostate cancer or testicular cancer which involves in removal of that part. There are different types of cancer surgeries: Preventive surgery: Preventive surgery is done to remove the suspected body tissue which is likely to become cancerous even though there is no sign of cancer at the time of surgery. It is also done in order to remove an entire organ when a person is at a high risk of having cancer in their lifetime. Diagnostic surgery: Diagnostic surgery is done to diagnose cancer. In this a part of tissue is taken and tested for presence of cancer. This is often called biopsy.
9
Staging surgery: Staging surgery is done to know how much the cancer has spread. Physical exam and imaging tests results are used to figure out cancer stage. But surgical stage gives more clear idea about the cancer stage. Curative surgery: Curative surgery is possible only when the cancer is found in one area and when it’s likely that all of the cancer can be removed by surgery. It may be used along with chemotherapy or radiation therapy before or after operation. Debulking surgery: This surgery is done to remove some part of tumour but not all. It’s done when removing the entire tumour would damage nearby tissues or organs. Remaining tumour is treating using radiation or chemotherapy. Palliative surgery: It is used to treat problems caused by advanced cancer. It is usually done to correct problems like discomfort or disability. Supportive surgery: Usually done to support other types of treatments Restorative surgery: This surgery is done after the main surgery in order to change the way a person looks. Radiation therapy It is also called as radiotherapy. Radiotherapy is used to destroy cancer cells or the tumour. Equipments are used to send high energy radiations and destroy the tumour cells. These 10
radiations destroy normal cells along with the cancer cells. But normal cells have the ability to repair themselves while cancer cells don’t. Radiation therapy does not always cure cancer; it is also used to reduce the growth of cancer cells. Radiotherapy utilizes high-energy gamma-rays which are emitted from metals such as radium or high-energy x-rays that are created in a special machine. Radiotherapy is given five times a week for about 10 weeks. But this depends on the type and size of the cancer. Radiation therapy has a number of side effects. Some people have side effects while others don’t show. Common side effects seen are: •
Fatigue
•
Skin changes
•
Loss of appetite
Other side effects seen are hair loss, cough, and sore throat. These side effects tend to stop after a while. Chemotherapy Chemotherapy means use of drugs to cure diseases. These drugs act by targeting the rapidly growing cells and damaging the DNA so that the cells commit suicide. Medicines travel throughout the body on administration and hence can be beneficial in metastasized cancer. Chemotherapy may also show side effects like hair loss, nausea, and loss of appetite, vomiting, fatigue.
11
Different types of chemotherapy drugs used: Chemotherapy drugs can be divided into various groups based on their mechanism of action, chemical structure. Alkylating agents Alkylating agents were one of the earliest classes of drugs used to treat cancer. Alkylating agents directly damage the DNA and prevent the cancer cells from reproducing. This class of drugs acts in any phase of cell cycle. Alkylating agents add an alkyl group to a DNA molecule and prevents the proteins from linking up hence causing a DNA strand breakage which eventually cause death of cancer cells. They are most effective in treating cancers that grow slowly like tumours and leukaemias. They are also used to treat ovarian cancer, lung cancer, breast cancer, sarcomas, lymphomas, myelomas and Hodgkin’s disease. There are five categories under alkylating agents: nitrogen mustards,
nitrosureas,
alkyl
sulfonates,
triazines
and
ethylenimines. Nitrogen mustards drugs under nitrogen mustards are Mechlorethamine sold under trade name Mustargen which is used to treat Hodgkin’s disease and non Hodgkin’s lymphoma, breast cancer and lung cancer. Ifosfamide marketed under the trade name Ifex used to treat Hodgkin’s and non Hodgkin’s lymphoma, Testicular cancer, germ cell tumours, sarcomas, lung cancer, bladder cancer, head and neck cancer, cervical cancer.
12
Melphalan sold under the brand name Alkeran also referred to as phenylalanine mustard. It is used to treat myeloma, ovarian cancer, neuroblastoma, and rhabdomyosarcoma and breast cancer. Chlorambucil sold under trade name Leukeran and is used to treat chronic lymphocytic leukaemia, malignant lymphomas, Hodgkin’s disease, breast cancer, ovarian and testicular cancer and choriocarcinoma. Cyclophosphamide which is marketed as Cytoxan or Neosar is used to treat Hodgkin’s and non-Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myelocytic leukaemia, acute myelocytic leukaemia, acute lymphocytic leukaemia, t-cell lymphoma, multiple myeloma, neuroblastoma, retinoblastoma, rhabdomyosarcoma, Ewing’s sarcoma; breast, testicular, endometrial, ovarian, and lung cancers. Nitrosoureas include drugs Streptozocin sold under the trade name Zanosar which is used to treat pancreatic cancer. Carmustine sold under the trade name BiCNU or BCNU, used to treat brain tumours, glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumours, multiple myeloma, Hodgkin’s disease, nonHodgkin’s lymphoma, melanoma, lung cancer, and colon cancer. Lomustine known as CCNU or CeeNU is used to treat primary and metastatic brain tumours, Hodgkin’s disease and non-
13
Hodgkin’s lymphoma, and has also been used for melanoma, lung, and colon cancer. Alkyl sulfonates: Busulfan, which is sold under the trade name Busulfex and Myleran, is used to treat myelogenous leukaemia. Triazines: Dacarbazine which is sold under the trade name DTIC-Dome is used to treat metastatic malignant melanoma, Hodgkin’s disease, soft tissue sarcomas, neuroblastoma, fibrosarcomas, rhabdomyosarcoma, islet cell carcinoma, and medullary thyroid carcinoma. Temozolomide sold under the trade name Temodar is used to treat brain tumours, anaplastic astrocytoma and glioblastoma multiform. Ethylenimines: Thiotepa which is known under the trade name Thioplex is used to treat breast cancer, ovarian cancer, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Altretamine is sold under the trade name Hexalen is used to treat ovarian cancer. Platinum drugs like cisplatin, carboplatin and oxalaplatin are grouped with alkylating agents as they act in the same way and kill cells. Antimetabolites Drugs under this class interfere with the growth of DNA and RNA by substituting for the normal building blocks of RNA or DNA. They are folic acid, purine or pyrimidine analogues and are
characterised
by
their
low
molecular
weights.
Antimetabolites induce cell death in S phase of cell growth 14
when incorporated into RNA or DNA. These drugs are used in treatment of leukaemia, breast, ovarian and gastro-intestinal cancers. Examples of antimetabolites include: •
5-fluorouracil
•
6-mercaptopurine
•
Capecitabine
•
Cladribine
•
Clofarabine
•
Cytarabine
•
Fluxuridine
•
Fludarabine
•
Gemcitabine
•
Hydroxyurea
•
Methotrexate
•
Pemetrexed
•
Pentostatin
•
Thioguanine
Anti-tumour antibiotics Anthracyclines are anti-tumour antibiotics which interfere with enzymes involved in DNA replication. These drugs are known to work in all the cell cycle phases and are used for a wide variety of cancers. These drugs can permanently damage the heart if given in high doses. Examples of anthracyclines include: •
Daunorubicin
•
Doxorubicin 15
•
Epirubicin
•
Idarubicin
Other anti-tumour antibiotics include: •
Actinomycin-D
•
Bleomycin
•
Mitomycin-C
Topoisomerase inhibitors As the name suggests these classes of drugs interfere with the enzyme topoisomerase which helps to separate the DNA strands so they can be copied. They are used to treat certain leukaemias, lung, ovarian, gastrointestinal and other cancers. Topoisomerase I inhibitors include: topotecan and irinotecan. Topoisomerase II inhibitors include: etoposide, teniposide and mitoxantrone. Vinca alkaloids These drugs are derived from the Madagascar periwinkle plant. These drugs are used to treat diabetes, hypertension and disinfectants. They are very effective as anti-cancer agents. There are four vinca alkaloids used clinically: vinblastine, vinorelbine, vincristine and vindesine. Vinca alkaloids are cytotoxic as the halt the cell division and cause cell death. Hormone therapy Drugs in this category are either sex hormones or hormonelike drugs that alter the production of male or female hormones. They are used to slow the growth rate of cancers of breast, prostate or endometrium. These drugs act by 16
preventing the body from making these hormones or by preventing the cancer cells from using hormones. Examples include: •
The anti-estrogens: fulvestrant, tamoxifen, toremifene
•
Aromatase
inhibitors:
anastrozole,
letrozole,
exemestane •
Progestins: megestrol acetate
•
Estrogens
•
Anti-androgens: bicalutamide , flutamide and nilutamide
•
Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH) agonists or analogs: leuprolide and goserelin
Immunotherapy Some drugs are used to stimulate the immune system so that it recognises the cancer cells and start destroying them. Some examples immunotherapies are: •
Monoclonal antibody therapy (passive immunotherapy), such as rituximab and alemtuzumab
•
Non-specific
immunotherapy
and
adjutants
(other
substances or cells that boost the immune response), such as BCG, interleukin-2 (IL-2), and interferon-alfa •
Immunomodulating drugs, for instance, thalidomide and lenalidomide
•
Cancer vaccines (active specific immunotherapies)
17
LUNG CANCER: Status: It is the second most common cancer for males and females behind cancers of the prostate and breast, respectively; according to the American Cancer Society, in 2008 it is estimated that there will be 215 020 new cases diagnosed and death due to lung cancer will claim some 161 840 lives, accounting for 29% of all deaths. According to the National Cancer Institute, the incidence of lung cancer increased by 28% & lung cancer is the commonest fatal cancer in many countries; in the United Kingdom in 2006 it accounted for 22% of deaths from cancer Drugs used: A new drug to treat advanced lung cancer has been approved by the U.S. Food and Drug Administration. Gilotrif (afatinib) is approved to treat patients with a specific subtype of of non-small cell lung cancer (NSCLC). About 85 percent of lung cancers are NSCLC, making it the most common type of lung cancer. In May, the FDA approved Tarceva (erlotinib) for treatment of patients with non-small cell lung cancer. Drugs Approved for Lung Cancer •
Drugs Approved for Non-Small Cell Lung Cancer
•
Drug Combinations Used to Treat Non-Small Cell Lung Cancer
•
Drugs Approved for Small Cell Lung Cancer
Drugs Approved for Non-Small Cell Lung Cancer 18
•
Abitrexate (Methotrexate)
•
Abraxane
(Paclitaxel
Albumin-stabilized
Formulation) •
AfatinibDimaleate
•
Alimta (Pemetrexed Disodium)
•
Avastin (Bevacizumab)
•
Bevacizumab
•
Carboplatin
•
Ceritinib
•
Cisplatin
•
Crizotinib
•
Docetaxel
•
Erlotinib Hydrochloride
•
Folex (Methotrexate)
•
Folex PFS (Methotrexate)
•
Gefitinib
•
Gilotrif (AfatinibDimaleate)
•
Gemcitabine Hydrochloride
•
Gemzar (Gemcitabine Hydrochloride)
•
Iressa (Gefitinib)
•
Mechlorethamine Hydrochloride
•
Methotrexate
•
Methotrexate LPF (Methotrexate)
•
Mexate (Methotrexate)
•
Mexate-AQ (Methotrexate)
•
Mustargen (Mechlorethamine Hydrochloride)
•
Paclitaxel 19
Nanoparticle
•
Paclitaxel Albumin-stabilized Nanoparticle Formulation
•
Paraplat (Carboplatin)
•
Paraplatin (Carboplatin)
•
Pemetrexed Disodium
•
Platinol (Cisplatin)
•
Platinol-AQ (Cisplatin)
•
Tarceva (Erlotinib Hydrochloride)
•
Taxol (Paclitaxel)
•
Taxotere (Docetaxel)
•
Xalkori (Crizotinib)
•
Zykadia (Ceritinib)
Drug Combinations Used to Treat Non-Small Cell Lung Cancer •
Carboplatin-Taxol
•
Gemcitabine-Cisplatin
Drugs Approved for Small Cell Lung Cancer •
Abitrexate (Methotrexate)
•
Etopophos (Etoposide Phosphate)
•
Etoposide
•
Etoposide Phosphate
•
Folex (Methotrexate)
•
Folex PFS (Methotrexate)
•
Hycamtin (Topotecan Hydrochloride)
•
Mechlorethamine Hydrochloride
•
Methotrexate
•
Methotrexate LPF (Methotrexate)
•
Mexate (Methotrexate)
•
Mexate-AQ (Methotrexate) 20
•
Mustargen (Mechlorethamine Hydrochloride)
•
Toposar (Etoposide)
•
Topotecan Hydrochloride
•
VePesid (Etoposide)
21
BREAST CANCER: Status: Breast cancer represents 14.0% of all new cancer cases in the U.S. In 2014, it is estimated that there will be 232,670 new cases of breast cancer and an estimated 40,000 people will die of this disease. Breast cancer is most frequently diagnosed among women aged 55-64. Drugs used: Common Chemotherapy Drugs for Breast Cancer Some of the most common chemotherapy drugs used to treat breast cancer includes the following: •
Anthracyclines: This class of drugs includes Adriamycin, Ellence, and Doxil
•
Taxanes: This class of drugs includes Taxotere, Taxol, and protein-bound Abraxane
•
Cytoxan
•
Xeloda and 5 fluorouracil (5 FU)
•
Navelbine
•
Gemzar
•
Herceptin: This drug is only of use in women whose breast cancers have the HER-2 gene
•
Other drugs may include Ixempra, Halaven, methotrexate (Rheumatrex, Trexall), Tykerb,and others.
For breast cancer, chemotherapy is given either by mouth or injected into a vein daily, weekly, or every 2-4 weeks.
22
There are many different chemotherapy drugs. The most common drugs and their combinations used to treat breast cancer are: •
AC
•
capecitabine (Xeloda)
•
CMF
•
docetaxel (Taxotere)
•
EC
•
E-CMF
•
eribulin (Halaven)
•
FEC
•
FEC-T
•
gemcitabine (Gemzar)
•
paclitaxel (Taxol)
•
vinorelbine (Navelbine)
Which type of chemotherapy is recommended for you will be based on individual factors such as: whether you have primary breast
cancer,
local
recurrence, regional
secondary breast cancer.
23
recurrence or
OVARIAN CANCER: Status: The chemotherapy drugs used to treat ovarian cancer are fairly standard. Typically doctors combine a platinum-based drug such as carboplatin (Paraplatin) or cisplatin with a taxane such as
paclitaxel
(Taxol)
or
docetaxel
(Taxotere).
New
chemotherapy (chemo) drugs and drug combinations are being tested. The drugs trabectedin (Yondelis) can have shown promise in some studies. Drugs used: Some of the other chemo drugs that are helpful in treating ovarian cancer include: •
Albumin bound paclitaxel (nab-paclitaxel, Abraxane)
•
Altretamine (Hexalen)
•
Capecitabine (Xeloda)
•
Cyclophosphamide (Cytoxan)
•
Etoposide (VP-16)
•
Gemcitabine (Gemzar)
•
Ifosfamide (Ifex)
•
Irinotecan (CPT-11, Camptosar)
•
Liposomal doxorubicin (Doxil)
•
Melphalan
•
Pemetrexed (Alimta)
•
Topotecan
•
Vinorelbine (Navelbine)
24
If cancer comes back less than 6 months after having chemotherapy, specialist may suggest one or more of the following treatments •
Paclitaxel alone, usually as a weekly treatment
•
Liposomal doxorubicin (Caelyx, Myocet or Doxil)
•
Gemcitabine
•
Cisplatin
•
Topotecan
•
Etoposide
•
Cyclophosphamide
25
ORAL CAVITY AND OROPHARYNGEAL CANCER: Status: In the UK between 2009 and 2011 in males, an average of 15% of cases were diagnosed in the 75+ age group, and 71% were diagnosed in the 50-74 age group. In females, an average of 29% of cases were diagnosed in the 75+ age group, and 59% were diagnosed in the 50-74 age. Drugs used: The chemo drugs used most often for cancers of the oral cavity and oropharynx are: •
Cisplatin
•
Carboplatin
•
5-fluorouracil (5-FU)
•
Paclitaxel (Taxol)
•
Docetaxel (Taxotere)
Other drugs that are used less often include • Methotrexate • Ifosfamide (Ifex) • Bleomycin Doctors are testing a combination of 3 newer chemotherapy drugs. These drugs are used in clinical trials for mouth and oropharyngeal cancers that have come back since they were first treated. These drugs are •
Docetaxel (Taxotere)
•
Paclitaxel (Taxol)
•
Gemcitabine (Gemzar)
26
CHEMOTHERAPY FOR ACUTE LYMPHOCYTIC LEUKEMIA: Status: Chemo for acute lymphocytic leukemia needs usage of a combination of anti-cancer drugs. They are given in 3 phases, usually over the course of about 2 years Drugs used: The most commonly used drugs include: •
Vincristine (Oncovin) or liposomal vincristine (Marqibo)
•
Daunorubicin (daunomycin or Cerubidine) or doxorubicin (Adriamycin)
•
Cytarabine (cytosine arabinoside, ara-C, or Cytosar)
•
L-asparaginase
(Elspar)
or
PEG-L-asparaginase
(pegaspargase or Oncaspar) •
Etoposide (VP-16)
•
Teniposide (Vumon)
•
6-mercaptopurine (6-MP or Purinethol)
•
Methotrexate
•
Cyclophosphamide (Cytoxan)
•
Prednisone
•
Dexamethasone (Decadron)
27
PROSTATE CANCER: Status: More than 1.1 million cases of prostate cancer were recorded in 2002, accounting for around 8percent of all new cancer cases and 15 percent in men. Age-adjusted incidence rates of prostate cancer have increased dramatically and this is largely because of the increased availability of screening for prostate-specific antigen (PSA) in men without symptoms of the disease. This test leads to detection of many prostate cancers that is small and/or would otherwise remain unrecognised, and which may or may not develop further into higher stage disease. Two thirds of cases of prostate cancer are diagnosed in more developed regions of the world. It is the second most common cancer in men worldwide. The highest incidence of prostate cancer was in Oceania and northern America; and the lowest incidence in Asia and Africa. Drugs used: Cancer drugs approved by the Food and Drug Administration (FDA) for prostate cancer are •
Abiraterone Acetate
•
Cabaitaxel
•
Docetaxel
•
Goserelin acetate
•
Jevtata
•
Prednisone
28
COLORECTAL CANCER: Status: Colorectal cancer is the third most common cancer in the world, with nearly 1.4 million new cases diagnosed in 2002. In 2012, republic of Korea had the highest rate of colorectal cancer, followed by Slovakia and Hungary. About 54 per cent of colorectal cancer cases occurred in more developed countries in both sexes. In men, Slovakia had the highest rate of colorectal cancer in 2012, followed by Hungary and republic of Korea. In women, Norway had the highest rate of colorectal cancer in 2012, followed by Denmark and the Netherlands. Drugs used: Drugs approved by FDA for treatment of colorectal treatment are •
Adrucil (Fluorouracil)
•
Avastin
•
Camptosar
•
Oxaliplatin
•
Cetuximab
•
Irinotecan hydrochloride
29
BLADDER CANCER: Status: Bladder cancer was the ninth most common cancer in the world, with 430,000 new cases diagnosed in 2012. It was three times more common in men compared with women. Smoking is a major cause of bladder cancer. Another cause is exposure to industrial chemicals, such as aromatic amines. Belgium had the highest rate of bladder cancer, followed by Lebanon and Malta. Drugs used: Drugs used by FDA for bladder cancer are •
Doxorubicin hydrochloride
•
Cisplatin
30
THYROID CANCER: Status Thyroid cancer is the 20th most common cancer in the UK (2011), accounting for less than 1 percent of all new cases. In females, it is the 18th most common cancer, whilst in males it is the 20th most common cancer. In 2011, there were 2,727 new cases of thyroid cancer in the UK.769 in men and 1958 in women giving a male: female ratio of around 10:25.1-4 the crude incidence rate shows that there are 3 new thyroid cancer cases for every 100,000 males in the UK, and 6 for every 100,000 females. Drugs used: Drugs approved by FDA for thyroid cancer are •
Docorubicin hydrochloride,
•
Caboantinib-s-malate,
•
Vandetanib,
•
Sorafenib
•
Tosylate.
31
Bibliography http://www.medterms.com/script/main/art.asp?articlekey=2580 accessed on: 8-9-14 http://www.medicinenet.com/kidney_cancer/page2.htm#what_is _cancer accessed on: 8-9-14 http://www.healthline.com/health/cancer accessed on: 8-9-14 https://pancreaticcanceraction.org/pancreaticcancer/diagnosis/faq/difference-benign-malignant-tumour/ accessed on: 8-9-14 http://www.cancer.org/cancer/cancerbasics/what-is-cancer accessed on: 8-9-14 http://www.medicalnewstoday.com/info/cancer-oncology/ accessed on: 9-9-14 http://www.cancer.org/cancer/cancerbasics/signs-andsymptoms-of-cancer accessed on: 9-9-14 http://www.healthline.com/health/cancer-warning-signs accessed on: 9-8-14 http://www.cancer.net/navigating-cancer-care/diagnosingcancer/stages-cancer accessed on: 10-9-14 http://www.medicaloncologyindia.com/index.php/history-ofcancer accessed on: 12-9-14 http://www.cancer.org/cancer/cancerbasics/thehistoryofcancer/t he-history-of-cancer-what-is-cancer accessed on: 12-9-14 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927383/ accessed on: 12-9-14 http://www.cancerresearchuk.org/cancerinfo/cancerstats/world/incidence/#Trends accessed on: 13-9-14 32
http://cancer-therapy.org/CT/v8/A/PDF/9.Ali_et_al_56-70.pdf accessed on: 13-9-14 http://www.cancer.org/cancer/showallcancertypes/index accessed on: 13-9-14 C.P. Kashyap et al; Human cancer cell lines- A brief communication; Journal of Chemical and Pharmaceutical Research; 2011; 3(6); 514-520 http://www.cancer.org/treatment/treatmentsandsideeffects/treat menttypes/surgery/surgery-how-is-surgery-used-for-cancer accessed on: 14-9-14 http://chemocare.com/chemotherapy/drug-info/NitrogenMustard.aspx#.VBXGA_mSwUY accessed on: 14-9-14 http://chemoth.com/types/alkylating accessed on: 14-9-14 http://www.cancer.org/treatment/treatmentsandsideeffects/treat menttypes/chemotherapy/chemotherapyprinciplesanindepthdiscussionofthetechniquesanditsroleintreatment/chemothe rapy-principles-types-of-chemo-drugs accessed on: 14-9-14 http://www.cancer.org/treatment/treatmentsandsideeffects/treat menttypes/chemotherapy/whatitishowithelps/chemo-what-it-isquestions-about-chemo accessed on: 14-9-14 http://chemoth.com/types/antimetabolites accessed on: 14-9-14 http://chemoth.com/types/vinca-alkaloids accessed on: 15-9-14
33
REVIEW OF LITERATURE THIAZOLE DERIVATIVES Ping Gong et al1, designed and synthesized a series of novel benzothiazole
derivatives
bearing
the
ortho-hydroxy
N
carbamoyl hydrazone moiety and were screened in vitro their cytotoxic activities against five cancer cell lines (NCI-H226, SKN-SH, HT29, MKN45, and MDA-MB-231). Among them, compounds 1a and compound 1b exhibited excellent antitumor activity with IC50values ranging from 0.14 μM to 0.98 μM against all cancer cell lines.
1a
1
1 6
+2
2 1 +
1 +
2
1
1b Teresa M.V.D. Pinho e Melo et al2,assayed thiazole compounds (2a, 2b) for their in vitro cytotoxicity on several human breast cancer cell lines (MCF7, HCC1954 and HCC1806 cell lines) and
34
also studied the effects of this two most active compounds on cell survival, viability, cell cycle, DNA damage and expression of proteins related to cell death pathways. The results for 4hydroxyphenyl substituted derivative, proved to be the most promising compound regarding HCC1806 cell line, a triple negative breast cancer.
2a2b Katia Z. Leal et al3, synthesized and evaluated benzothiazole hydrazones for their in vitro antiproliferative activity against three human cancer cell lines: HL-60 (leukemia), MDAMB-435 (breast)
and
HCT-8
(colon).
They
observed
significant
cytotoxicity for the three cancer cell lines and theoretical profile of compounds 3a and 3bpointed them as promising lead molecules for anticancer drug design.
35
3a
3b Chun-Hao Yang et al4, designed, synthesized and evaluated two series of novel 2-substituted 5,7-dihydroxyanthra[2,1d]thiazole-6,11-dione derivatives from naturalrhein for their antitumour activities against human cancer cell lines A549 and HeLa in vitro. They found sixteen compounds were more potent than rhein especially compound4, and this compound could be a useful lead structure for developing new rhein analogues with antitumor activity.
36
4 Andreas Reichel et al5, explored library of approximately 250,000 thiazole-based compounds as inhibitors of Cdc7 kinase activity in cancer cells and found compound 5as potent, selective Cdc7 inhibitor that decreased phosphorylation of the direct substrate MCM2 in vitro and in vivo, and inhibited DNA synthesis and cell viability in vitro.
5 Zheng fang Yi et al6, synthesized and evaluated a series of 2,3diaryl-4-thiazolidinone derivatives
for
their
antiproliferative
properties against two well-known cancer cell lines (A549 as human lung cancer and MDAMB-231 as human breast cancer). The compound 6a &compound 6bwas indicated to suppress tumor growth and metastasis as well as promote survival rate
37
and results suggested that the new series of 2-(3-(arylalkyl amino
carbonyl)phenyl)-3-(2-methoxyphenyl)-4-thiazolidinone
derivatives could be regarded and developed as novel highly potential anticancer agents in the future.
6a-b
Compound
R
6a
4-Br-Ph(CH2)2NH-
6b
4-Cl-Ph(CH2)2NH-
Sherif A.F. Rostoma et al7, synthesized and evaluated thirty thiazole compounds for their preliminary in vitro anticancer activities. Nine derivatives were tested for their preliminary in vitro anticancer activity and reported Compound 7b revealed a broad spectrum of anticancer activity against tumor cell lines. Also, compounds 7b, 8b, 9f and 10 could be considered as promising dual anticancer antibiotics.
38
7a-b Compound
R
7a
Cyclo-C6H11
7b
C6H5
8a-b
Compound
R
8a
Cyclo-C6H11
8b
C6H5
9a-b
39
Compound
R
9a
CH3
9b
Cyclo-C6H11
9c
CH2C6H5
9d
C6H5
9e
4-CH3-C6H4
9f
4-F-C6H4
10 Ahmed
R.
Ali
et
al8,
synthesized
a
series
of
imidazo[2,1b]thiazoles bearing pyrazole moieties 11-13 (a-c). Eleven compounds were screened for anticancer activity at a single dose (10 mM) and in vitro anticancer evaluation revealed that compounds11-13(a) exhibited increased potency towards cancer cell lines.
11a-c
40
12a-c
13a-c Compound
R
11a,12a, 13a
H
11b, 12b, 13b
Cl
11c, 12c, 13c
CH3
San-Qi Zhang et al9, found out that combination of the fragment of 2-substituted-3-sulfonylaminobenzamide with the fragment of 2-aminobenzothiazole or 2-aminothiazolo[5,4-b]pyridine, or 2amino[1,2,4]triazolo[1,5-a]pyridine
produced
the
novel
structures of anticancer agents. As a result, nineteen target compounds
were
synthesized,
characterized
&
their
antiproliferative activities in vitro were evaluated against four human cancer cell lines including HCT-116, A549, MCF-7 and
41
U-87 MG. The results suggested that compound 14 can block PI3K/AKT/mTOR pathway and significantly inhibit tumor growth. ) 2 +1
6
0H2
2 + &
+1 2
6 1
1+ $F
14 Hai-Liang Zhu et al10, synthesized a series of compounds which contain
pyrazole,
thiazole
and
naphthalene
and
their
antiproliferative activity, EGFR inhibitory activity, cytotoxicity and inhibition to HeLa cell migration were evaluated. They were reported Compound 15as the most potent inhibitory activity (IC50 = 0.86 μM for HeLa and IC50 = 0.12 μM for EGFR) and further docking simulation of compound 15 into EGFR active site showed it may be developed as a potential antitumor agent.
15
42
Alex Joseph et al11, synthesized a series of novel 5-alkyl/aryl thiadiazole substitutedthiazolidin-4-ones by a two-step process & compounds were screened for in vitro antiproliferative activity on human breast adenocarcinoma cells (MCF-7) by MTT assay. Among the compounds tested, they found compound 16a, 16b, 16c to be the most active derivatives with IC50values of 46.34, 66.84, and 60.71 ȝmol L–1, respectively.
16a
16b
43
16c Hai-Hong Wang et al.12,synthesized series of novel thiazole derivatives (17a-17t) and found that compound 17f displayed the most potent inhibitory activity for HER-2 and antiproliferative activity against MCF-7 and B16-F10C6 and thus would be a potential anticancer agent.
17f Abbas Shafiee et al13, synthesized and investigated a series of cis-restricted thiazole analogues(18a-f) of combretastatinA-4 for inhibition of cell proliferation against three cancer cell lines, HT29, MCF-7, and AGS, and a normal mouse fibroblastic cell line, NIH-3T3, using an MTT assay. They study showed 2(methylthio) substituted compounds 18c and 18e showed little cytotoxic activity against the four cell lines in contrast, the presence of the 2-(benzylthio) group on the thiazole ring
44
(compound 18d & 18f) resulted in a significant improvement in cytotoxic activity.
18a-f compound
R
R1
18a
H
CH3
18b
H
CH2Ph
18c
Cl
CH3
18d
Cl
CH2Ph
18e
F
CH3
18f
F
CH2Ph
Ahmed Kamal & Manika Pal-Bhadra et al14, synthesized and evaluated a series of benzothiazole–pyrrole based conjugates (19a–o) for their antiproliferative activity. They concluded that compounds such as 19a, 19b, 19c, 19d–g, 19j, 19k, 19m and 19oexhibited significant cytotoxic effect in the MCF-7 cell line and interestinglycompounds19m and 19o are effective in causing apoptosis in MCF-7 cells.
45
19a-c Compound
R1
R2
R3
19a
H
Me
H
19b
H
OMe
H
19c
19d-g Compound
R1
R2
R3
19d
H
F
H
19e
H
OMe
H
19f
H
NO2
H
46
19g
19h-l Compound
R1
R2
R3
19h
H
Me
H
19i
H
F
H
19j
H
OMe
H
19k
H
NO2
H
19l
Saeed Emami et al15, designed a series of 3-(trimethoxyphenyl)2(3H)-thiazole thiones as new heterocyclic analogue of combretastatin A-4 and evaluated them for cytotoxic against human cancer cell lines T47D, MCF-7 and MDA-MB-23. They demonstrated that compound20showed the highest activity against all cell lineswith no significant toxicity towards non tumoral cells MRC-5 and compound20depolymerized tubulin,
47
inhibited cell proliferation, and induced apoptosis in cancer cells.
20 Kamal M. Dawood et al16, synthesizedN-(4-(Pyrazol-4-yl)thiazol2-yl)-N0-phenylthiourea derivative and then treated with variety of hydrazonoyl chlorides under basic condition at reflux to afford the
corresponding
2-(4-(pyrazol-4-yl)thiazol-2-ylimino)-1,3,4-
thiadiazole derivatives 21, 22a-e and 23a-e. Most of the synthesized compounds were tested for anticancer activity against human hepato celluar carcinoma HepG2, human breast cancer MCF-7 and human lung cancer A549and found 22e were the most potent derivatives, displaying IC50values of 8.438 uM.
21
48
22a-e
23a-e Compound
R
22a, 23a
C6H5
22b, 23b
4-ClC6H4
22c, 23c
4-MeC6H4
22d, 23d
4-OMeC6H4
22e, 23e
4-NO2C6H4
Devarajan Karunagaran et al17, develop novel anticancer compounds by synthesizing diaminoindoloylthiazoles (24a-c) and diaminocinnamoylthiazoles (25a,b) as analogs based on a
49
topsentin scaffold and investigated the cytotoxic and apoptotic activities of these compounds in HeLa cells. The results suggest that compound 24c is the most cytotoxic against HeLa cells (IC50 1 μM) and very effective in inducing apoptosis of HeLa cells. Thus, this compound promising anticancer effects that warrant further investigation.
24a-c Compound
R1
R2
24a
H
4-ClC6H4
24b
4-ClC6H4
4-MeOC6H4
24c
H
4-MeOC6H4
25a
50
25b Robert Kiss & Gilbert Kirsch et al18, carried out in vitro growth inhibitory activity of 26 thiazoles on a panel of 6 human cancer cell lines and showed that compound26 was efficacious against purified guinea pig kidney preparations that mainly express the NAK alpha-1 subunit which is also expressed in gliomas, melanomas and non-small-cell lung cancers.
26 Min Ji et al19, designed and synthesized three series of novel 4benzothiazole amino quinazolines Dasatinib derivatives. The compounds were investigated for their in vitrocytotoxic activity against human cancer cell lines(HCT-116, DLD1, K562, U937, A549, NCI-H661). They reported most significant inhibition was achieved for compound 27& thus they may be promising lead compounds to be developed as an alternative for Imatinibresistant patients.
51
+&
1 +1
+ 1
6
2
1
+&
1
2
+&
& +
1
2
27 Lingaiah Nagarapu et al20, synthesized a novel series of building
blocks
consisting
of
benzo[4,5]thiazolo[1,2-
a]pyrimidine-3-carboxylate as potential anticancer compounds. These compounds were evaluated for cytotoxicity against human cancer cell lines in vitro (A549, HeLa, MDA-MB-231 and MCF-7).
The
results
displayed
Compound
28bexhibited
promising cytotoxicity with IC50 values of 0.58 and 1.58 μM specifically against human breast adeno carcinoma cell lines, MCF-7
and
MDA-MB-231,
while
compound
28ashowed
promising cytotoxicity against MDA-MB-231 (IC50 value of 5.01 μM).
28a
52
28b Ahmed R. Ali et al21, synthesized a novel series of acetamide derivatives
possessing
both
2-imino-4-arylthiazoles
morpholine and characterized by IR,
1
H NMR,
13
and
C NMR,
elemental and mass spectral analyses. Among the compounds tested, compounds 29a and 29b were found to be the most active candidates & assessment of toxicities, drug likeness, and drug score profiles of compounds 29a and 29bare promising.
29a
29b
53
Teresa M.V.D. Pinho e Melo et al22, reported synthesis and biological evaluation of 6,7-bis(hydroxyl methyl)-1H,3H-pyrrolo [1,2-c] thiazoles as anticancer agents against MCF7 breast cancer cell lines. They suggested compound 30as the lead compound due to its good performance against MCF7 breast cancer cell lines (IC50= 1.0 μM)
30 Romeo Romagnoli et al23, found that the substituents at the C2and C5-positions of 3,4,5-trimethoxyphenyl had a profound effect on antiproliferative activity. The 2-N-methylamino thiazole derivatives 31a, 31b and 31c were the most active compounds as antiproliferative agents on MCF-7 cells, with IC50 values from low micromolar to single digit nanomolar. In addition, they are also active on multidrug-resistant cell lines and, the most active compound 31cinduced apoptosis.
31a-c
54
compound
R1
R2
31a
NHCH3
4'-Me-C6H4
31b
NHCH3
4'-OMe-3'-F-C6H3
31c
NHCH3
4'-OEt-C6H4
Ahmed Kamal & Anthony Addlagatta et al24, synthesized and evaluated a series of chalcone-amidobenzothiazole conjugates for their anticancer activity. The results displayed all these compounds exhibited potent activityagainst different cancer cell lines with two potential compounds (32a and 32b). Flow cytometric analysis revealed that these compounds induced cell cycle arrest at G2/M phasein A549 cell line leading apoptotic cell death & study also demonstrates the synthesis of chalconeamidobenzothiazole conjugates as promising anticancer agents.
32a
32b
55
Xian-Hui Yang et al25, designed and synthesized a series of 1,3,4-thiadiazol-2-amide derivatives, and evaluated them as potential antiproliferation and FAK inhibitors. Among all the compounds, 33 showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.45 and 0.31 μM, respectively & also exhibited significant FAK inhibitory activity (IC50 = 5.32 μM). The results demonstrated compound 33 with potent FAK inhibitory activity may be a potential anticancer agent.
33 Mirjana Popsavin et al26, synthesized 2-(b-D-xylofuranosyl) thiazole-4-carboxamide (34) and two new tiazofurin analogues with 5-hydroxymethyl-2-methyl-tetrahydro-furo[2,3-d][1,3]dioxol6-ol moiety as a sugar mimic (35a and 35b) and evaluated for their in vitro antitumour activity against a panel of human tumour cell lines (K562, HL 60, Jurkat, Raji and HeLa). Flow cytometry data suggest that cytotoxic effects of analogue 33 in the culture of K562 cells might be mediated by apoptosis. All three analogues 34, 35aand 35b were also active against Jurkat, Raji and HeLa cells, with IC50 values in the range from 0.06 to 5.61 μM. 56
34
35a
35b Hussein I. El-Subbagh et al27, designed and synthesized a novel series of 2-acetamido- or 2-propanamido-4-(4-substituted phenyl)-1,3-thiazoles.They
subjected
Compounds
in
vitro
assessment for their antitumor activity, at a single dose of 10 μM and investigated that most of the compounds exhibits broadspectrum antitumor activity. Compounds 36a and 36b believed to be the most active members and proved to be nine and sevenfold more active than the standard antitumor drug 5-FU, respectively.
57
36a +&
1 6
2 1 +
&+ &O
36b Ravindra
M.
Kumbhare
&
Manika
Pal-Bhadra
et
al28,
synthesized and evaluated a new series of isoxazoles and triazoles linked 2-phenyl benzothiazole for their anticancer activity. They tested compounds for their cytotoxicity, apoptotic activity and its inhibitory activity against three cancer cell line. Among all, compound37 showed promising cytotoxicity against Colo-205 and A549 cells& hence this compound has the potential that it can be selected for further biological studies.
58
37 Mark J. Kurth et al29, utilized a versatile Cu-catalysedazide– alkyne click reaction (CuAAC) on tautomeric benzo [4,5]thiazolo [3,2-d] tetrazole and 2-azidobenzo [d]thiazole starting materials and synthesized a number of (1H-1,2,3-triazol-1-yl) benzo [d] thiazoles. One of the resulting products of this investigation, triazol benzo [d] thiazole (38), was found to possess significant neuroprotective activity in human neuroblastoma (SH-SY5Y) cells.
38 Ke Ding et al30, identified a new series of 2-substituted thiazole carboxamides as potent pan inhibitors againstall three isoforms of Akt. One of the most potent compounds, 39, inhibited the kinase activities of Akt and also potently inhibited the
59
phosphorylation of downstream MDM2 and GSK3ȕproteins and displayed strongly antiproliferative activity in prostate cancer cells. Thus inhibitors might serve as lead compounds for further development of novel effective anticancer agents
39 Hussein I et al31, designed and synthesized a novel series of 2acetamido and 2 or 3-propanamido derivatives of 4- or 5substituted-thiazoles. They elucidated the structure of the newly synthesized compounds by the use of 1H &13C NMR, and Mass spectrometry. Compounds were subjected to NCI in vitro assessment for their antitumor activity, Compounds 40a, 40b and 40c exhibited broad spectrum antitumor activity to the Leukemia CCRF-CEM cell line.
40a-c
60
compound
R1
R2
R3
n
40a
phenyl
H
Cl
2
40b
phenyl
H
N-phenyl-piperazino
1
40c
phenyl
H
N-phenyl-piperazino
2
Hussein I. El-Subbagh et al32, designed and synthesized a novel series of thiazolo [2,3-b] quinazoline, and pyrido[4,3-d] thiazolo [3,2-a] pyrimidine analogues. The obtained compounds were evaluated for their in vitro antitumor activity at NCI. Compounds 41, 42b, 42c and 42d showed remarkable broadspectrum antitumor activity. Compounds 41 and 42a are almost nine fold more active than 5-FU; while 42band 42care almost seven fold more active than 5-FU.
41
61
42a-c compounds
R
R1
R2
R3
42a
H
H
OCH3
H
42b
H
OCH3
OCH3
H
42c
CH3
OCH3
OCH3
H
Te-Chang Lee & Tsann-Long Su et al33, synthesized a series of novel thiazoles derivatives and the antiproliferative activity of these agents against human leukemia and various solid tumor cell growth in vitro was studied. Studies on the therapeutic effect against human breast carcinoma showed that complete tumor remissions (CR) were achieved by treating with compound 43a and 43b. The present studies generated a series of new potent DNA inter strand cross-linking agents, which have potential for further antitumor drug development.
62
43a
43b Samir Bondock et al34,described the synthetic strategies and characterization of some novel thiazole derivatives carrying different pharmacophores and heterocyclic rings that are relevant to potential antitumor activities. The antitumor activities of the newly synthesized compounds were evaluated. The results revealed that compound 44displayed promising in vitro antitumor activity &incorporating a thiazole ring to 1,3,4oxadiazole skeleton resulted in better antitumor activities than those displayed by the pyrazole and thiophene ring systems.
63
44 Ahmed Kamal et al35, synthesized and evaluated a series of combretastatin-amidobenzothiazole
conjugates
for
their
anticancer activity. All these compounds exhibited significant anticancer activity and the most potent compound 45 showed GI50 values ranging 0.019-11 μM. Compound 45 showed significant effect on tubulin polymerization and affected the ERK signalling pathway that result in the decreased levels of ERK1/2, p-ERK and c-Jun proteins. Docking experiments have shown that the active molecules interact and bind well in the ATP binding pocket of ERK protein.
45 Shijun Zhang et al36, synthesized and biologically characterized a series of 2,5-disubstituted-thiazolidine-2,4-dione analogues based on the newly identified lead 46a,a potential anticancer agent via the inhibition of the Raf/MEK/extracellular signal
64
regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades. They identified a new lead structure, 46b, was to have improved antiproliferative activities& to induce apoptosis in cancer cells. Collectively, these results strongly encourage further optimization of 46b as a new lead with multi-target properties to develop more potent compounds as anticancer agents.
46a-b compound
R
46a 45b
Ke Dinget al37, designed and synthesized a series thiazole derivatives as new Bcr/Abl inhibitorsby hybriding the structural moieties from FDA approved imatinib, nilotinib and dasatinib. They observed new inhibitors strongly suppressed the activity of Bcr/Abl kinase and potently inhibited the proliferation of K562 and KU812 leukemia cancer cells& Compound 47 displayed
65
comparable potency with that of nilotinib in both biochemical kinase assay and cancer cell growth inhibition assay. These inhibitors might serve as lead compounds for further developing new anticancer drugs.
47 Romeo Romagnoli et al38, reported a one-pot procedure for the preparation of a novel 2-(N-pyrrolidinyl)-4-amino-5-(30,40,50trimethoxybenzoyl)thiazole in which the size of the substituent at the C-2 position of the thiazole ring plays an essential role in compound activity. The most active agent 48 inhibited tubulin polymerization and treatment of HeLa cells resulted in their arrest at the G2-M phase of the cell cycle. Furthermore, compound 48was effective against multidrug resistant cancer
66
cells & indicated that compound 48is a promising new antimitotic agent with encouraging preclinical potential.
48 Chang-Hyun Oh et al39, synthesized a series of 18 new thiazole derivatives and their in vitro antiproliferative activities against A375P human melanoma cell were tested. Compounds showed superior potency against A375P& compounds49a and 49b exerted sub-micromolar IC50 values over 7 (including A375P) and 6 melanoma cell lines, respectively. They also reported ADME profiling, in silico toxicity, drug-likeness, and drug score data of compounds 49aand 49b are promising.
49a-b
67
compound
R1
R2
48a
H
H
48b
H
2-OH
Keykavous Parang & Abbas Shafiee et al40, synthesized a number
of
N-benzyl
substituted
(((2-morpholinoethoxy)
phenyl)thiazol-4-yl) acetamide derivatives containing thiazole and evaluated for Src kinase inhibitory activities They found, unsubstituted N-benzyl derivative (50a) showed the inhibition of c-Src kinase and inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. 4-Fluorobenzylthiazolyl derivative (50b) exhibited 64-71% inhibition in the cell proliferation of BT-20 and CCRF cells at concentration of 50 μM.
50a-b compound
R
50a
H
50b
4-F
68
Subhas S. Karki & Sathees C. Raghavan et al41, reported Levamisole, the imidazo[2,1-b]thiazole derivative as a potential antitumor agent. They synthesized, characterized and evaluated biological activity of its novel analogueswith substitution in the aralkyl group and on imidazothiadiazole molecules with same chemical backbone but different side chains on leukemia cells. The cytotoxic studies showed that 51a, 51b, and 51c exhibited strong cytotoxicity while others had moderate cytotoxicity&51b induced apoptosis without cell cycle arrest suggesting that it could be used as a potential chemotherapeutic agent.
.
51a
51b
51c
69
Dalip Kumar & Kavita Shah et al42, synthesized a series of 3,5bis(indolyl)-1,2,4-thiadiazoles and evaluated for their cytotoxicity against
selected human cancer cell
lines.
Among
the
synthesized bis(indoly)-1,2,4-thiadiazoles, the compound 52 with 4-chlorobenzyl and methoxy substituent’s
showed the
most potent activity.
Compound 52 Marco A. Cerbón et al43, evaluated one thiazolo[5,4-b]quinoline derivate 52 to determine its relative cytotoxic activity in tumoral versus non-tumoral cells, as well asthe cell death mechanism induced on K-562 human leukemia cells.It was found to be more cytotoxic to tumor cells & induces cell death without previous cell cycle arrest at any phase. In conclusion, the significant cytotoxicity of compound 53 together with the cell death type justifies further evaluation of this compound in the effort to find new and highly specific anti-tumor agents against leukemia cells.
70
53 Gaëtan L. A. Mislin et al44,synthesizedfour molecules and shown to chelate iron(III) efficiently with a 1:1 stoichiometry. The results
displayeddithioamide
BHPTC
(54)as
promising
antiproliferativeactivity in several cancerous cell lines HCT116, HT29, MCF7, A549, HL60,K562, making this molecule an interesting lead compound for the design of new iron-chelating anticancer drugs.
54 Wei-Xiao Hua et al45, synthesized Thirty-seven (E)-1-(4-methyl2-arylaminothiazol-5-yl)-3-arylprop-2-en-1-ones
via
Claisen-
Schmidt condensation. All these thiazolyl–chalcones were characterized and evaluated by MTT assay on human cancer cell lines in vitro. Compounds 55a, 55b, 55c, 55d and 55e are effective against cancer cell lines with IC50s below 10 μM. The antitumor activity in ICR mice bearing sarcoma 180 tumors 71
indicates compounds 55ehave moderate in vivo activity with 22–25% tumor-weight inhibition.
55a-c compound
R1
R2
55a
3,4-Cl
H
55b
3,4-Cl
3-OCH3
55c
2-CH3
3,4,5-OCH3
55d
3-Cl
3-OCH3
55e
3-Cl,4-F
3,4,5-OCH3
K.S. Rangappa et al46, designed, synthesized a series thiazole moiety to elucidate the Structure Activity Relationship (SAR) studies on the anti-leukemic activity and evaluated for their antileukemic activity by trypan blue exclusion, MTT, LDH assays and cell cycle analysis. Results suggest that the meta and para substitution of thiazole derivatives 56a-eshowed significant inhibition against K562 cells.
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2
5
1 1+ +1
6
56a-e Compound
R
56a
56b
56c 56d
56e
Alireza Foroumadi et al47, synthesized a series of substituted 2phenylthiazole-4-carboxamide derivatives as potential cytotoxic agents and evaluated against three human cancer cell lines including T47D (Breast cancer), Caco-2 (Colorectal cancer) and HT-29 (Colon cancer). It was found that substitution at the 4position by a methoxy group (57a) led to improvement of activity
73
against Caco-2 cells while 2-methoxy substituent (57b) could maintain the high activity against HT-29 and T47D cell lines Also, 3-fluoro analogue (57c) showed significant cytotoxic activity profile against all cell lines with IC50 values less than 10 mg/mL.
57a
57b
57c Valentin Zaharia et al48, synthesized a series of novel ptoluenesulfonyl-hydrazinothiazoles and hydrazine-bis-thiazoles derivatives by initial condensation & further acylation reaction.
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They confirmed structures of newly synthesized derivatives by IR,
1
H-NMR, EIMS spectral data and elemental analysis.
Compounds 58a-d and 59 showed significant anticancer activities (IC50
