Accepted Manuscript Synthesis of enamino-2-oxindoles via conjugate addition between α-azido ketones and 3-alkenyl oxindoles: Cytotoxicity evaluation and apoptosis inducing studies Niggula Praveen Kumar, Yogesh Vanjari, Sowjanya Thatikonda, Venkatesh Pooladanda, Pankaj Sharma, Balasubramanisan Sridhar, Chandraiah Godugu, Ahmed Kamal, Nagula Shankaraiah PII: DOI: Reference:
S0960-894X(18)30618-8 https://doi.org/10.1016/j.bmcl.2018.07.038 BMCL 25969
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date: Revised Date: Accepted Date:
27 April 2018 12 June 2018 26 July 2018
Please cite this article as: Kumar, N.P., Vanjari, Y., Thatikonda, S., Pooladanda, V., Sharma, P., Sridhar, B., Godugu, C., Kamal, A., Shankaraiah, N., Synthesis of enamino-2-oxindoles via conjugate addition between α-azido ketones and 3-alkenyl oxindoles: Cytotoxicity evaluation and apoptosis inducing studies, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.07.038
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Bioorganic & Medicinal Chemistry Letters
Synthesis of enamino-2-oxindoles via conjugate addition between α-azido ketones and 3-alkenyl oxindoles: Cytotoxicity evaluation and apoptosis inducing studies Niggula Praveen Kumar,a Yogesh Vanjari,a Sowjanya Thatikonda,b Venkatesh Pooladanda,b Pankaj Sharma,a Balasubramanian Sridhar,d Chandraiah Godugu,b* Ahmed Kamal,a,c* Nagula Shankaraiaha* a
Department of Medicinal Chemistry, bDepartment of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India c School of Pharmaceutical Education and Research, Jamia Hamdard University, New Delhi 110062, India d Laboratory of X-ray Crystallography, CSIR-Indian institute of Chemical Technology, Hyderabad-500007, India
ARTICLE INFO
ABSTRACT
Article history: Received Revised Accepted Available online
A facile method for the construction of double bond between 3-ylidene oxindoles and α-azido ketones has been successfully accomplished with a mild base. This method features azido reduction with concomitant double bond formation to provide the new class of bioactive enamino-2-oxindoles. These new compounds were screened for their in vitro cytotoxic potential on selected human cancer cell lines such as colon, lung, breast, and cervical cancer cells. Among them, representative compounds 3a, 3h, 3k, 3p, 3w and 3x showed notable cytotoxicity profile with IC50 values ranging from 1.40±0.10 to 28.7±0.36 µM. Compound 3k displayed most potent cytotoxicity against lung cancer (NCI-H460) cells with an IC50 value of 1.40±0.10 µM. 3k also arrested the G2/M phase of the cell cycle and induced distinctive apoptotic features on lung cancer cells. The apoptosis induction is supported by various cellular assays such as AO/EB, DAPI, and DCFDA staining studies including clonogenic assay. Extent of apoptosis was also analyzed by Annexin binding and JC-1 staining. Moreover, this method is amenable for the generation of a library of new class of stable bioactive enamino-2-oxindoles.
Keywords: Enamino-2-oxindoles conjugate addition C=C bond formation azido reduction cytotoxicity Apoptosis
Cancer is one of the lethal diseases worldwide and characterized by abnormal cell proliferation leading to malignant tumors which may invade other tissues through metastasis. 1 At present, chemotherapy is the effective way to combat cancer. Majority of the cytotoxic compounds are aimed to target the apoptotic pathways and cell divison.2 The oxindole based scaffolds represent a privileged class of heterocyclic compounds that have been extensively studied owing to their medicinal importance3 and their flexibility to serve as building blocks.4 These class of molecules have been reported to display a wide range of biological activities such as anticancer, anti HIV, antidiabetic and anti-bacterial activities.5
Moreover, oxindoles which contain heteroatom attached to alkene also play an important role within the class of functionalized oxindoles. Particularly, the structural modifications at C-3 and C-5 positions of the indolin-2-one ring have led to many derivatives with enhanced antitumor activity. 8 Therefore, search towards novel strategies for the construction of new biologically important compounds have always been of considerable interest in synthetic/medicinal chemistry.9
Various research groups have reported the anticancer potential of 2-oxindole derivatives. Attempts that have been made to explore cytotoxic oxindole derivatives had lead to the development of a marketed anticancer drug sunitinib (Figure 1), which is mainly used to treat gastrointestinal tumors and metastatic renal cancer.6 Two endogeneous molecules isatin and 5-hydroxy-oxindole present in body fluids were found to have antiproliferative activity.7 Authors to whom correspondence should be addressed. Corresponding author; Dr. Nagula Shankaraiah, E-mail:
[email protected];
[email protected] Dr. Ahmed Kamal, E-mail:
[email protected] Dr. Chandraiah Godugu, E-mail.:
[email protected]
Figure 1. Structures of oxindole containing bioactive molecules and newly synthesized enamino-2-oxindoles.
1
In the present scenario, conjugate additions10 are regarded as one of the crucial C–C bond forming reactions aids in straightforward access to various functionalized molecules. 11 3Ylidene oxindoles serves as an efficient Michael acceptor and are continuously explored substrates. In the past, Duan and coworkers developed an organocatalyst-mediated conjugate addition of acetylacetone to 3-ylidene oxindoles to obtain a new class of oxindoles (Scheme 1).12 Recently, Liu et al also reported base-catalyzed reaction of 3-ylideneoxindoles with O-Boc hydroxy carbamates for the synthesis of amidoacrylates. 13 On the other hand, the α-azido ketones represent synthetically useful organic azides owing to their double reactivity in C–C bond formation.14 Their synthetic feasibility has been exploited in various inter and intramolecular fashion to build numerous building blocks, pharmaceuticals and natural products.15 Moreover, the reduction of azido functionality into an amine which is attached to ɑ-carbon is a precious organic transformation.16 Hence, there lies an immense need to identify new strategies for the synthesis of bioactive oxindoles. In continuation of our earlier efforts in developing new domino protocols towards the synthesis of bioactive oxindoles by exploring 3-alkenyl oxindole as key substrates,17a herein we wish to report a base-mediated conjugate addition of α-azido ketones to the 3-ylideneoxindoles resulting in a variety of new enaminooxindoles. Furthermore, this methodology not only aids in C–C bond formation but also concomitant azido reduction resulting in the synthesis of cytotoxic amino indolinones. Furthermore, we have also explored the in vitro cytotoxicity and apoptosis inducing ability of these new compounds.
Table 1. Screening of various bases and solvents for the conjugate addition between 3-ylideneoxindole and α-azido ketones
entry
base
solvent
time (h)
yield (%)b
1
-
MeOH
48
NRc
2
Et3N
CH2Cl2
2
53
3
K2CO3
MeOH
12
