Aryl- and Heteroaryl-Thiosemicarbazone Derivatives ...

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Aryl- and Heteroaryl-Thiosemicarbazone Derivatives and Their Metal Complexes: A Pharmacological Template Narayana S.H.N. Moorthy*, Nuno M.F.S.A. Cerqueira, Maria J. Ramos and Pedro A. Fernandes REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, s/n, Rua do Campo Alegre, 4169-007 Porto, Portugal Received: July 4, 2012; Accepted: September 6, 2012; Revised: September 6, 2012

Abstract: In this review, we discuss the current patents concerning aryl/heteroaryl thiosemicarbazone derivatives as regards to their activities and properties, including coordination (chelation) properties. The mode of action of the aryl/heteroaryl thiosemicarbazone derivatives involves metal coordination with proteins or biological fluids that have metal ions in their structure. Additionally, these molecules can also form multiple hydrogen bonds through their (thio) amide and N3 nitrogen that ensure a strong interaction with the receptor. In some cases, strong - interactions can be observed too. Special attention is given to pyridyl, bis-pyridyl, benzoylpyridyl and isatin thiosemicarbazone derivatives that exhibit significant anticancer, antiviral and other activities in free and in metal complexed forms. This key biological role is often related with their capability to inhibit the enzyme ribonucleotide reductase, similar to what is observed with potent anticancer drugs such as Triapine and methisazone. Recent studies have revealed that thiosemicarbazone can also inhibit topoisomerase II enzyme. Thiosemicarbazone derivatives form coordination complex with various metals such as Zn, Cu, Fe, Co, Ni, Pt, Pd, etc., and these complexes provide better activities than the free thiosemicarbazones. Recent patents show that the controlled or sustained release dosage form of the thiosemicarbazone derivatives along with ionizing radiations is used for the treatment of proliferative diseases (US20110152281, US20110245304, US20120172217).

Keyword: Cancer, DNA, isatin, ribonucleotide reductase, thiosemicarbazones. INTRODUCTION Thiosemicarbazones (TSC) constitute an important class of N, S-donor ligands that have been studied for a considerable period of time. Thiosemicarbazone derivatives have a wide range of biological activities and are used for the treatment of many diseases. First reports on their medical applications began to appear in the fifties against tuberculosis and leprosy [1-3]. In the sixties, they started to be tested as anticancer (1956) and antiviral drugs (1973) [4, 5]. The antitumor activity of these thiosemicarbazones seems to be related with the inhibition of DNA synthesis produced by a modification in the reductive conversion of ribonucleotides to deoxyribonucleotides. From this period, the worldwide commercialization of methisazone (N-methylisatin-thiosemicarbazone) started and showed high effectiveness against smallpox and vaccinia viruses [6-9]. Additionally, 2-formylpyridine thiosemicarbazone showed a strong anti-leukemic effect [4]. N-Carbamoyloxy urea (NH2-C(=O)NH-O-C(=O)NH2) is a reactive intermediate of hydroxy urea (HU) (NH2C(=O)NH2) and a structural analog of hydrazones and semicarbazone (bioisosteric replacement of -NH-O-C(=O)by -NH-NH-C(=O)-), with significant cytotoxic activity *Address correspondence to this author at the REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, s/n, Rua do Campo Alegre, 4169-007 Porto, Portugal; Tel/Fax: +351-220 402 506; E-mail address: [email protected]; [email protected] 1574-8928/13 $100.00+.00

(RNR inhibitory activity) [10, 11]. Hydrazones (R1R2 C= NNH2) are a product of the reaction of hydrazine with ketones or aldehydes (Eqn. 1), in which an oxygen is replaced with the =NNH2 functional group. Semicarbazones are obtained from the condensation of a ketone or aldehyde and a semicarbazide (Eqn. 2). Thiosemicarbazone, S-alkyl thiosemicarbazones and selenosemicarbazones are structural analogs of semicarbazones but diverge by the substitution of an oxygen atom by sulfur, thioalkyl and/or selenium atoms (groups) respectively [12]. R-CHO (or) R1-CO-R2 + NH2-NH2 R-C(=N-NH2) or R1C(=N-NH2)R2 ------- Eqn. 1 H2NNHC(=O)NH2 + RCHO (or) RC(=O)R R2C=NNHC (=O)NH2 (or) RCH=NNHC(=O)NH2 ------- Eqn. 2 Thiosemicarbazone: RCH=NNHC(=S)NH2

R2C=NNHC(=S)NH2

(or)

Selenosemicarbazone: RCH=NNHC(=Se)NH2

R2C=NNHC(=Se)NH2

(or)

S-alkyl thiosemicarbazone: R2 C=NNHC(-S-alkyl)NH2 (or) RCH=NNHC(-S-Alkyl)NH2 The success observed in the mode of action of these thiosemicarbazones has prompted for further pharmacological developments. For example, Triapine (3-aminopyridine2-carboxaldehyde thiosemicarbazone) (3-AP) is being developed as an anticancer drug and is currently at phase II clinical studies for several types of cancer [13, 14]. 3-Amino-4© 2013 Bentham Science Publishers

2 Recent Patents on Anti-Cancer Drug Discovery, 2013, Vol. 8, No. 2

methylpyridine-2-carboxaldehyde thiosemicarbazone (3AMP) is an analogue of Triapine that is showing much better therapeutical effects against L1210 leukemia, M-109 lung carcinoma and A2780 human ovarian carcinoma cell lines [15]. The biological activities of thiosemicarbazones involve interaction with metal ions and a number of mechanisms of action have been identified including the inhibition of the enzyme ribonucleotide reductase (RNR), metal dependent radical damage (ROS (reactive oxygen species) generator), DNA binding, topoisomerase II inhibition, mitochondria disruption, inhibition of protein synthesis and recently multidrug resistance (MDR) protein inhibition [16-26]. In this review, we have focused on the patents and development of the thiosemicarbazone scaffolds (template) and their role for anticancer and other activities. THIOSEMICARBAZONE DERIVATIVES Bis-pyridyl Thiosemicarbazones The di-2-pyridylketone thiosemicarbazone (DpT) derivatives (Table 1) belong to the bis-pyridyl thiosemicarbazone family and demonstrate that some compounds of this class exhibit selective antitumor activity (in vitro (cell lines) and in vivo) by RNR inhibition [23, 26-30]. Among the DpT derivatives, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) is an active lead compound (tridentate ligand) utilizing the pyridyl nitrogen, nitrogen (thio amide) and sulfur atoms as donor atoms (N,N,S system), which complete the coordination shell of iron by binding in a 2:1 chelator to iron ratio. Dp44mT produces antiproliferative activity by various mechanisms such as generation of cytotoxic radicals, up-regulation of the growth and metastasis suppressor NDRG1 (N-myc down regulated gene-1), etc. [25, 31]. Furthermore, some of the DpT ligands were found to induce iron dependent •OH-mediated strand-breaks in plasmid DNA. Reports have revealed that the Dp44mT-iron complex has an ability to produce •OH in redox cycle. However, in those cases, no systemic iron-depletion was detected in Dp44mT-treated animals, probably because of the utilization of low doses of Dp44mT to induce antitumor activity. This also evidenced that low doses of Dp44mT-iron complexes are not able to generate hydroxyl radicals in the animal models [22, 27, 32-40]. These results have shown that apoptosis induced by Dp44mT on NB4 cells (acute promyelocytic leukemia cell line), have markedly less effect on nonproliferating cells and is significantly more effective than DFO (desferrioxamine mesylate). Dp44mT also induces apoptosis in several types of acute leukemia and multiple myeloma cell lines, causing a G1/S arrest (the cyclin deficient cells arrest the border between the G1 and S phase of the cell cycle) in cancer cells but not in normal non-cycling cells i.e. PBMCs (peripheral blood mononuclear cells) [25, 41]. It also selectively kills breast cancer cell (MDA-MB231) than healthy mammary epithelial cells (MCF-12A) by G1 cell cycle arrest [42]. Benzoylpyridyl Thiosemicarbazones The benzoylpyridyl thiosemicarbazone (BpT) groups of Fe-binding drugs (Table 1) represent a promising class of antitumor agents [25, 34, 39-44]. The increased antineoplas-

Moorthy et al.

tic activity of the BpT series can be attributed to lower redox potentials of their Fe complexes than their corresponding DpT-Fe and NBpT-Fe (2-(3-nitrobenzoyl) pyridine thiosemicarbazone) complexes. In fact, the unsubstituted phenyl moiety in the BpT series contributed toward the lowered Fe(III/II) redox potentials of the BpT-Fe complexes, leading to higher redox activity [34]. The NBpT series of compounds has higher redox potential than the BpT series and the incorporation of an electron-withdrawing group (i.e., -NO2) increased the redox potential of the NBpT-Fe complexes. This redox potential is detrimental to the redox activity of the complex and it is in agreement with previous studies using other Fe chelators [34, 45-47]. This clearly indicates that the introduction of the nitrophenyl group in the NBpT series of chelators decreases the antiproliferative efficacy [34, 45-47]. Contrarily, the Fe complexes of the ApT (2-acetyl pyridine thiosemicarbazone) series, which have an electron-donating methyl substituent at the C6 position, demonstrated the lowest Fe(III/II) redox potentials [48]. Pyridyl Thiosemicarbazones (PTSC) The thiosemicarbazones with pyridine substituent provided clinical improvements to triapine and related compounds (Table 1). The substitution of a hydrogen atom by a methyl group at the R2 position results in an enhancement of the complex stability. However, dimethylation of the terminus nitrogen of the thiosemicarbazones (R3) increases the antiproliferative effect. Indeed, the PTSC (monomethylated at position R3) is considered to be the most effective metal ion binder among the reported TSCs. The Cu(II) and Zn(II) complexes of TSCs also provided stable complexes as with other metal ions (such as Fe) [49, 50]. However, these PTSCs do not exert a measurable effect on the redox potential, but have the highest impact on the stability of the complexes as well as the cytotoxicity, especially in the absence of a pyridine-NH2 group in the molecule [51]. Triapine is a potent RNR inhibitor that is currently in clinical trials for cancer chemotherapy [50]. In comparison, the hydroxyurea quenches the tyrosyl free radical in the M2 subunit of the enzyme, while Triapine is an iron chelator [52, 53]. Because of the requirement of iron to regenerate the tyrosyl free radical in the M2 subunit, sequestration of iron by Triapine may account for its enhanced potency against RNR compared with hydroxyurea [54-56]. Preclinical data also indicates that Triapine may also yield the greatest benefit when combined with other DNA damaging or cytotoxic agents. In vitro and/or in vivo studies revealed that Triapine enhances the activity of various DNA-damaging agents and nucleoside analogues [51, 56-58]. Isatin Thiosemicarbazones Isatin derivatives have been reported for various biological activities such as anticancer and antiviral activities specifically for their action against pox virus, vaccinia, rhinovirus, Moloney leukemia virus and SARS viruses, etc. [59-62]. The derivatives of isatin thiosemicarbazones have been reported for MDR modulation activity in cancer cells. Pglycoprotein (P-gp) modulating activity of 60 compounds were reported and among them 10 compounds have the

Aryl and Heteroaryl Thiosemicarbazones

Table 1.

Recent Patents on Anti-Cancer Drug Discovery, 2013, Vol. 8, No. 2

Structure of Some Thiosemicarbazone Derivatives Substituted with the Pyridine Rings. Structure

Name/Abbreviations

Ref.

Bis-pyridyl thiosemicarbazone [25, 127] N

H N

R

N S

N

Di-2-pyridylketone thiosemicarbazone (DpT) backbone R = -N(CH 3)2

Dp44mT

[25, 127]

R = -NHCH 3

Dp4mT

[25, 127]

Benzoylpyridyl thiosemicarbazone [44, 127]

R1 H N

N R2

N S

N

2-Benzoylpyridine-3-thiosemicarbazone (BpT) backbone NO 2

[27, 48]

R1 H N

N R2

N S

N

2-(3-nitrobenzoyl) pyridine thiosemicarbazone (NBpT) Backbone Pyridyl thiosemicarbazones R1

[8, 50] S N

N

R3 N H

N

R2

R3

2-Pyridinyl thiosemicarbazone (PTSC) Backbone R1 = H, R2 = H, R3 = H

2-Formyl pyridine thiosemicarbazone (FPTSC)

[3, 8, 25, 50]

R1 = NH 2, R2 = H, R3 = H

Triapine (3-AP)

[8, 25, 50] [48]

S N N

R1 N H

CH 3

N R2

2-acetylpyridine-3-thiosemicarbazone (ApT Backbone)

3


Moorthy et al.

thiosemicarbazone functional group exhibit an inverse P-gp expression action (MDR1-selective agents), and 7 compounds such as NSC73306, NSC658339, NSC716765, NSC716766, NSC716768, NSC716771 and NSC716772 are composed of the 1-isatin-3-thiosemicarbazone moiety (Table 2) [25, 60].

cells with intrinsic or acquired P-gp induced MDR and indirectly acts to eliminate resistance in MDR1substrates [64]. This occurs by two separate, but closely related, mechanisms. First, the cytotoxicity of NSC73306 is directly proportional to the levels of functional P-gp. Second, P-gp expression decreases in cells treated with NSC73306, which renders cells sensitive to the P-gp substrates against which they had previously shown resistance [64]. Although it is not a substrate or modulator for some of the ABCC (ABCC1, ABCC4, and ABCC5) transporters implicated in conferring MDR, this compound interacts with ABCG2 with high affinity [65]. The interaction between NSC73306 and the ABCG2 active site(s) was confirmed by its stimulatory effects on ATPase activity (140-150 nM), but there is no interaction to be reported with MRP1 (multidrug resistant protein), MRP4 or MRP5. The coordination complex of the molecule showed that it forms N,S bidentate and N,S,O tridentate coordinations through the ind-2-one oxygen of the isatin ring. Zinc coordination complex of the molecules did not influence MDR-selective activity even though it (zinc(II)) forms a more stable complex than iron(II) (in accordance with the Irving-Williams series) [9, 59, 63-66].

Methisazone is a well known and the first thiosemicarbazone of the isatin thiosemicarbazone derivative used as an anticancer and antiviral agent. The reported literature on these isatin thiosemicarbazone derivatives revealed that the presence of isatin and halogen groups could improve the Pgp targeted selectivity, which serves as a foundation in the search for potential drugs. The predictions of cytotoxicity and MDR1 selectivity, constitute valuable tools that will aid in the design of new MDR1-selective cytotoxins based on isatin thiosemicarbazones [9, 25, 61, 62]. The effective drug on the above tested series, NSC73306, exhibits selective cytotoxicity in P-gp expressing drug resistant carcinoma cells. NSC73306 does not interact with P-gp as either substrate or inhibitor, whereas Triapine (a TSC RNR inhibitor devoid of MDR-selective activity) is actively effluxed by P-gp [59, 63, 64]. Furthermore, NSC73306 kills Table 2.

Structures of Some Isatin Thiosemicarbazone Derivatives Structure

Name/Abbreviations R1

Ref [8]

S N N H

R3 N H

N R2

O

isatin--thiosemicarbazones backbone R1 = H, R2 = CH 3, R3 = H

Methisazone

[8]

R1 = H, R2 = H, R3 = (4-OCH3 )Phenyl

*NSC73306

[8, 64, 65]

R1 = H, R2 = H, R3 = CH=C(COOC2H 5)2

NSC658339

[8]

R1 = NO 2, R2 = H, R3 = CH2CH=CH 2

NSC716765

[8]

R1 = NO 2, R2 = H, R3 = C6H5

NSC716766

[8]

R1 = NO 2, R2 = CH2-N-morpholinyl, R3 = CH 2CH=CH2

NSC716768

[8]

R1 = Br, R2 = H, R3 = (4-F) Phenyl

NSC716771

[8]

R1 = Br, R2 = H, R3 = (4-NO2 ) Phenyl

NSC716772

[8]

N-methylisatin--thiosemicarbazone derivative SCH-16

[67]

O

CH 3

O N

CH3

N O

N NH2

H 3C

O N

N N NO2

*NSC is National Service Center


Structurally NSC73306 is similar to methisazone and composed of a 4-methoxy phenyl substituent on the Nterminal end of the thiosemicarbazone pharmacophore. Methisazone has a methyl substitution on the nitrogen atom in the isatin nucleus. Structure activity relationship (SAR) analysis showed that electron withdrawing groups (such as NO2) and electronegative atoms in the phenyl ring of the isatin nucleus provides significant activities [25, 60]. Nmethylisatin--thiosemicarbazone derivative SCH-16 has a therapeutic effect against pox viruses, Moloney leukemia viruses and recently against HIV [67]. It also exhibited in vitro antiviral activity against Japanese encephalitis virus (JEV) and West Nile virus (WNV) infections [67]. The SAR analysis showed that an appropriate modification in the aryl ring of the isatin moiety provides effective JEV inhibition [67]. Other Thiosemicarbazones Derivatives Thiosemicarbazone derivatives substituted with different aryl/heteroaryl rings other than pyridyl and isatin rings are also reported in the literature and exhibit significant pharmacological activities [68-82]. A novel class of -D-glucopyranosyl thiosemicarbazone derivative has inhibitory activity against glycogen phosphorylase b (GPb) (Table 3) [68]. The mechanistic studies on the complex structures revealed that the inhibitors are accommodated at the catalytic site with the glucopyranosyl moiety at approximately the same position as the -D-glucose and stabilize the T conformation of the 280s loop of the enzyme. This compound fits tightly into the -pocket, a side channel from the catalytic site with no access to the bulk solvent [68-71]. The carbocycle and heterocycle substituted semicarbazones and thiosemicarbazones are used for the treatment of neurological disorders such as neuronal damage following global and focal ischemia, prevention of neurodegenerative conditions and otoneurotoxicity (Table 3). These derivatives are also used as anticonvulsant, antimanic depressants, local anesthetics, diabetic neuropathy and urinary incontinence [72, 73]. 5-Nitrofuryl-containing thiosemicarbazones derivatives have trypanocidal activity and the 5-nitrofuryl moiety found to be the pharmacophore group of Nfx. The 3-(5nitrofuryl) acroleine thiosemicarbazone-platinum complexes showed in vitro anti-Trypanosoma cruzi activity. These compounds could act as dual inhibitors in the parasite, through production of toxic free radicals and interaction with DNA [74, 75]. The 3,5-diacetyl-1,2,4-triazol bis(4-methylthiosemicarbazone) (H5L2) and its dinuclear platinum(II) complex [Pt(m-H3L2)]2 provided in vitro antiproliferative activity against NCI-H460, A2780 and A2780cisR human cancer cell lines [76]. Cyclodextrin derivative of aryl thiosemicarbazone and semicarbazone derivatives are reported to have anticonvulsant, antinociceptive, anti-inflammatory and antiangiogenic activities. Earlier literatures revealed that these aryl thiosemicarbazone and semicarbazone derivatives also have anticancer and antiviral activities on various cancer cell lines and viruses respectively [77-79]. Cytotoxic evaluation of S-methyl derivatives of thiosemicarbazone (S-methyl N1,N4-di(salicylidene) isothiosemicarbazones) were reported by several researchers [80, 81], re-


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vealing that the 4-methoxy thiosemicarbazones-Fe chelates have considerable activity against K562 cell lines and 3methoxy thiosemicarbazones-nickel chelate exhibited a cytotoxic effect against ECV304 and K562 cell lines. These results revealed that the presence of methoxy groups on the aromatic ring increase the selectivity of the cytotoxicity [77, 80-82]. 5-Formyluracil thiosemicarbazone is another thiosemicarbazone derivative patented very recently, which has SNO ligand atoms coordinated to copper [83, 84]. The presence of substituents on the thiosemicarbazidic chain strongly affects the DNA interaction of this thiosemicarbazone and its metal complexes. The free NH2 group in this thiosemicarbazone moiety seems to play an important role in DNA binding [83]. Various aryl substituted thiosemicarbazone derivatives were patented by Barsanti et al., especially those having potent antiviral activity including HCV infection and immunopotentiators [84]. COORDINATION CARBAZONES

PROPERTIES

OF

THIOSEMI-

Thiosemicarbazones as well as semicarbazones can form 1-4 coordination bonds with metal ions. Additionally, these molecules have a capacity to create multiple hydrogen bonds with their (thio) amide and N3 nitrogen atom [85] (Figs. 1ad). The presence of azomethine carbon, - to a homo or heterocyclic ring, there is a possibility of hydrogen bonding. In the latter case, the non-covalent bonding potential often further increases the possibility of - stacking interactions, generally due to the flat or almost flat structure [85-87]. Thiosemicarbazones are typically excellent chelators of transition metals such as iron, copper, zinc, gallium, palladium, platinum, nickel, cobalt, etc. [88-91]. Kowol and coworkers reported the gallium(III) complexes of five different thiosemicarbazones, and among them, the N4-disubstituted R-N-heterocyclic thiosemicarbazones-gallium(III) complex ([Ga(L)2]PF6) exhibits significant cytotoxicity in low nanomolar concentration. The iron(III) complex of the ligand showed less activity (in micromolar range) than the metalfree ligands and its gallium complex [92]. As per their studies, they have described that the iron(III) complex destroys the tyrosyl radical in RNR, followed by the metal-free ligands released in contrast to the corresponding gallium(III) complexes [92-94]. The antimicrobial activity (targeting bacteria, fungi and viruses) of the thiosemicarbazones metal complexes was also reported. Horton and Varela [95] reported that 3-deoxy-Derythro-hexos-2-ulose bis(thiosemicarbazone) coordinates with three metal ions such as copper(II), platinum(II), and palladium(II) and has potential use against the poliovirus type 1. Later, Genova et al. [96] synthesized the palladium(II) complex of benzyl bis-thiosemicarbazone and 3,5diacyl-1,2,4-triazol bis-(4-methylthiosemicarbazone), which has antiviral activity against herpes simplex virus strain 1 and 2 on acyclovir resistant cells [97]. The [bis-(citronellalthiosemicarbazonato)nickel(II)] and [aqua (pyridoxylthiosemicarbazonato)copper(II)] chloride monohydrate, showed antiviral activity against retroviruses HIV-1 and HTLV-1/-2 [97]. The Co(II), Ni(II) and Cu(II) complexes of the thiosemicarbazone derivatives of 2-hydroxy-8-R-


Table 3.

Moorthy et al.

Structures of Thiosemicarbazone Derivatives Substituted with Different Aryl/heteroaryl Rings Structure

Name/Abbreviations

Ref

Aromatic aldehyde 4-(-Dglucopyranosyl-thiosemicarbazone

[68]

NSC669341

[8]

R = 4-NO2

NSC695331

[8]

R = 3-Cl

NSC695333

[8]

Aryl/heteroaryl thiosemicarbazones

[72, 73, 83, 84]

Aryl/heteroaryl thiosemicarbazones

[76]

Napthyl thiosemicarbazone (NT) backbone

[127]

S-methyl N1,N 4-di(salicylidene) isothiosemicarbazones

[77,80,81]

OH

O

HO

H N

H N N

HO OH

N

Ar

S

S

H N

Cl N H

N H

NH

H 3C CH 3

N

S N

R N N H

N H

O

R1 X A2

A1

R2

R3

N

N

N

R4 Y

A1, A 2= Aryl, R1,R2,R3,R4 = Aryl or Alkyl, X, Y =O or S R1

R

H

R2

N

N

N

R3 X

R,R1 ,R2 ,R3 = Aryl or Alkyl, X =O or S N

S N

OH R

N

R1

R2

H3 C

OH

R

HO S

N N

N

tricyclo[7.3.1.0.2,7]tridecane-13-one such as [Cu(LC6H5)2] and LC6H5 ligands provided pronounced activity towards Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli [98]. Copper is one of the most important chelating metals and can occur in two oxidation states Cu(I) and Cu(II). Copper(I) forms monomeric, dimeric, tetrameric and hexameric complexes via an S-donor complex and adopts either trigonal planar or distorted tetrahedral geometry. Copper(II) forms monomers, dimers, tetramers and polymers with distorted

R1

tetrahedral, square planar, square pyramidal or octahedral geometries [99, 100]. New polymeric copper(II) complexes of thiosemicarbazone based ligands, including the pyrazolone ring, can also form tridentate chelate ligands using the same coordination as SNO donor set. One of the complexes of the same ligand gives significant cytotoxicity against various cancer cell lines [101-103]. Copper complexes with bis-(thiosemicarbazone) ligands, were first synthesized in the 1950s, [104] and the bisthiosemicarbazones can bind in neutral as well as anionic



7

O R2

M O R1

N N N

H S

H H 3C

A)

B)

N

N

NH

CH 3

N N

S Fe

N

S

CH 3 H N

N

N N

CH3 S

N

H3 C

N N H

N

Fe Fe N

C)

D)

Fig. (1). Coordination between different thiosemicarbazones (A-D) and respective metal ions.

forms using both of their arms. Recent studies on these copper complexes showed that they have anticancer, superoxide dismutase-like activity, which has been used as positron emission-imaging agents for blood perfusion and tissue hypoxia using radiolabelled complexes [105, 106]. Antiviral activity was also observed against HIV in four bis(thiosemicarbazonate)gold(III) complexes [Au(L)]Cl such as glyoxal-bis-(N4-methylthiosemicarbazone), glyoxal-bis-(N4ethylthiosemicarbazone), diacetyl-bis-(N4- methylthiosemicarbazone) and diacetyl-bis-(N4-ethylthiosemicarbazone) [107]. The neutral and the anionic thiosemicarbazones form tetrahedral Zn(II) complexes. Zinc(II) forms [ZnX2(HL)2] and [ZnL2] complexes with a slightly distorted, square pyramidal mixed–ligand complex [ZnL(tmen)] with a tridentate O,N,S thiosemicarbazone and N,N,N,N-tetramethylethylenediamine (tmen). The thiosemicarbazone ligand is dinegative O, N3, S-donor in the former, and uninegative N4, N3, S-donor in the latter complex [100, 108]. Revenco et al. has synthesized and characterized the coordination behavior of palladium and nickel complexes of S-

methyl N1,N4-di(salicylidene) isothiosemicarbazones [80, 81]. They described that the ligand in different configurations using either O, N, and S or O, N, and N donor atoms for coordination, this coordinated complex enhances the reactivity of H2L molecules [109]. Additionally, nickel(II) or copper(II) salts of S-methyl N1,N4-di(salicylidene) isothiosemicarbazones and 2-formylpyridine were developed with the general formula [NiL1]2 and [CuL2]2 [110]. Gerbeleu et al. also studied the metal coordination behavior (Cu, Ni, Co) of salicylaldehyde S-alkylthiosemicarbazone and selenosemicarbazones, which have antiproliferative activity [111-113]. Pyridoxal N(4)-substituted thiosemicarbazone and its gold(I) complex [Au(PEt3)] showed cytotoxicity against cisplatin sensitive cell line (A2780) and cisplatin-resistant cell line (A2780cis) (10 times potent); those activities are similar to the reference drug cisplatin. The platinum squared planar complex [PtLCl] of 2-acetyl pyridine thiosemicarbazone–N–Me also possessed cytotoxicity against cisplatin sensitive cell line (A2780) and cisplatin-resistant cell line


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Fe(II)-PKIH complexes undergo reaction with the protein. When oxygen-containing hydrazide portion of the PKIH analogues is converted to the sulfur-containing thiosemicarbazone moiety (DpT series) (Table 1), the antineoplastice activity is improved [34, 117]. Among the thiohydrazone analogs shown in Table 4, the O,N,S thiohydrazones exhibited lesser antiproliferative effects and redox potency than their parent aroylhydrazones. However, the N,N,Sthiohydrazones form reversible Fe(III/II) complexes, which acquire higher antiproliferative activity than hydrazone analogues that have similar potency to the thiosemicarbazones [117]. For instance, the iron chelating property and the carcinostatic activity of acylhydrazone and thiosemicarbazones derived from salicylaldehyde and 1-napthol-carboxaldehyde respectively, were displayed through RNR inhibition. RNR is a critical enzyme in the cell cycle and it is one of the ratelimiting steps in DNA synthesis [43, 118-121]. The thiosemicarbazone derivatives bind to the non-heme iron in the M2 subunit of the enzyme with high affinity, and preclude the formation of a tyrosyl radical that is essential for the enzyme activity. Recent studies suggest that potent RNR inhibitors of this class of thiosemicarbazone include -(N)-heterocyclic carboxaldehyde thiosemicarbazones (HCTs), and the N*-N*S* structural motif of thiosemicarbazones is detrimental for RNR inhibition. These HCT derivatives have shown to be 80-5000 times more potent than hydroxyurea and are active against a wide spectrum of transplanted rodent neoplasms as

(A2780/Cp8) (0.08 and 0.14 μM); these activities are better than the cisplatin. Nickel and cobalt complexes of 5formyluracil thiosemicarbazone were found to be less active than the corresponding copper(II) complex against the human leukemic cell lines (K562 and CEM) [100, 114]. Salicylaldehyde thiosemicarbazone (H2saltsc) reacts with [M(PPh3)3X2] (M=Ru, Os; X=Cl, Br) provided the [M(PPh3)2(Hsaltsc)2] complex and the ligand coordinates to the metal as a bidentate N,S-donor, yielding a fourmembered chelate ring [115]. Triapine (metal-free ligand) and its iron(III), gallium(III), zinc(II) and copper(II) complexes exhibit in vitro cytotoxic activity by acting on the diferric/tyrosyl radical center of the RNR enzyme [116]. The result showed that the iron(III) complex does not chelate the protein bound iron, which may cause reactivation of the RNR enzyme. However, the decreased cytotoxicity was observed on the copper(II) complex, due to its high stability at physiological pH and its redox properties. The zinc(II) and gallium(III)-ligand (Triapine) complex possessed lower conditional stability constants at physiological pH, resulting in more potent cytotoxicity, similar to that of free Triapine [116]. The di-2-pyridylketone isonicotinoyl hydrazone (PKIH) analogs (Table 4) have moderate antiproliferative activity (IC50 = 1-42 μM) against the SK-N-MC neuroepithelioma cell line. These PKIH analogs utilize an N,N,O-donor set for the coordination property and the C=N-Fe group of the Table 4.

Structures of Hydrazone and Thiohydrazone Derivatives and Respective Abbreviations Structure

Name/Abbreviations

Ref

Hydrazones [25, 117, 127] N

H N

R

N O

N

Di-2-pyridylketone isonicotinoyl hydrazone (PKIH) analogs R= 4-Pyridyl

PKIH

R= C6H5

PKBH

R= (3-Br) C 6H4

PKBBH

R= 2-Thiophene

PKTH Thiohydrazones R1-(C=S)N-N=C(R2,R3 )

[117]

Thiohydrazone (TH) backbone Pyridoxal thiobenzoyl hydrazone

H2PTBH

Salicylaldehyde thiobenzoyl hydrazone

H2STBH

2-Hydroxy-1-naphthaldehyde thiobenzoyl hydrazone

H2NTBH

Di-2-pyridylketone thiobenzoyl hydrazone

HPKTBH

2-Benzoylpyridine thiobenzoyl hydrazone

HBPTBH



9

well as spontaneous lymphomas of dogs [122-129]. The cytotoxicity of the terminal dimethylated (TD) amine in the -N-heterocyclic thiosemicarbazones and their metalcontaining complexes (e.g. the gallium complex KP1089) is higher by about 1000-fold activity than its corresponding free amino group. These compounds are also substrates for ABCC1 and ABCG2, which have better active efflux properties than thiosemicarbazones lacking terminal dimethylation. This may be due to the lipophilic property of the TD compounds, which might be associated with stronger affinity to hydrophobic binding sites in the ABCC1 leading to more effective drug export [130]. Quantitative structure activity relationship (QSAR) analysis, pharmacophore analysis and docking studies on various thiosemicarbazone derivatives have shown that the van der Waals (vdW) surface area properties such as the surface polarity, hydrogen bond donor properties and hydrophilic contact surface of the molecules are important for the RNR inhibitory activity. Those results obtained from the pharmacophore analysis revealed that the H-bond acceptor and H-bond donor along with aromatic or planar ring in the molecules and concentrated hydrophobicity in a particular region are responsible for the activity. The distance between the aromatic/hydrophobic and the PiN (normal aryl/heteroaryl rings) sites to the H-bond donor and the acceptor groups should be connected with almost the same distance (Fig. 2 and 3). The pharmacophore distances between the contours of Triapine (Fig. 3) show that the hydrophobic and hydrophilic sites (acceptor) separated by a large distance and other polar properties such as donor and acceptor are located within a 3Å radius. It revealed that these polar regions are responsible for the chelating property of the molecules. In Fig. (2), the polar regions of the molecules are concentrated within some radius, further away from the hydrophobic regions. The flexibility and polar property in the thiosemicarbazone region allows the molecule to coordinate to the metal ion present in the enzyme (Fig. 1a-d). The active site of the RNR exhibits aromatic residues (tyrosine) and a Fe ion, hence flexible aromatic rings with polar bridge (thiosemicarbazones) are necessary for the interactions. The molecular docking results obtained in a recent work suggested [116, 131, 132] that the ligands could only interact with the oxidized form of iron in the R2 subunit of the protein, i.e. after activation of the enzyme. In the reduced form, the metallic center is protected by a cluster of aspartates and glutamate residues, which hinders the access of the inhibitors to the metallic center. These results also show that iron interacts very closely with the nitrogen atoms from the thiosemicarbazones (Fig. 4). The sulfur atom is also close to this center, but the results have shown that it might not be fundamental for the chelating property of these compounds [31, 132-138]. The thiosemicarbazone derivatives with other substituents (bis-pyridyl, benzoylpyridyl, isatin and pyridyl) have significant biological activities. SAR analysis of these thiosemicarbazone derivatives have shown that chelators containing hard electron donors such as oxygen, typically lead to ligands that bind Fe (III) with high affinity that do not have pronounced antitumor efficacy. In contrast, ligands

Fig. (2). Flexialigned structure of reference (Triapine, PIH and 311) and the data set of thiosemicarbazone derivatives along with their pharmacophore site.

Fig. (3). Pharmacophore distance of Triapine.

Fig. (4). The binding mode of one thiosemicarbazone in the R2 subunit of RNR (PDB entry: 1MXR). The results were obtaining with autodock software and the VsLab plug-in.

with soft donors such as sulfur and nitrogen can undergo a redox cycle and induce a “double punch”, namely marked chelation and redox activity. Such compounds include the thiosemicarbazone chelators such as Triapine and the ApT, BpT, and DpT series [89, 139].


The nitrogen atom in the pyridine molecules coordinates to the metal ions along with the imine and thio atoms of the thiosemicarbazone pharmacophore (Fig. 1). The isatin thiosemicarbazone derivatives have MDR modulating activity in addition to antiproliferative and antiviral activities. The computational analysis results on the thiosemicarbazone derivatives show that the flexibility of the bonds and distance between the aryl groups are responsible for the RNR inhibitory activities through coordination bonding with the metal ions present in the enzymes. CURRENT & FUTURE DEVELOPMENTS Since 1950, thiosemicarbazones are among the iron chelators that have received considerable attention because of their wide pharmacological utility that includes antineoplastic, antibacterial, antiviral and antifungal activities. The mechanism of action of these compounds has shown to involve cellular iron depletion, arrest at the G1/S phase of the cell cycle and promotion of cell apoptosis. Recent developments in the field have improved the knowledge on thiosemicarbazones and they have become the first class of chelators to be comprehensively assessed as antineoplastic agents against cancer cells, and in clinical trials. In this context, they have an impressive ability to inhibit the growth of a variety of tumors and show selectivity for certain molecular targets. The thiosemicarbazones are worthy candidates to investigate in terms of developing novel anticancer agents. A number of thiosemicarbazone derivatives showed high antiproliferative activity, better than DFO. Considering the suboptimal properties of Fe chelation of DFO and its pronounced anticancer activity, the development of more effective chelators against cancer is of paramount importance. So far, Triapine (Vion Pharmaceuticals, New Haven, CT) is being evaluated in human phase II clinical trials as an antineoplastic therapeutics. Other ligands under development include some members of the PIKH class (e.g. 311) and tachpyr (N,N’,N"tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane) that are also showing promising results in several types of tumors. Tachpyr is a metal chelator that depletes intracellular iron (binds Fe(II) and readily reduces Fe(III)), and its chelated form (Fe(II)-Tachpyr)) undergoes intramolecular oxidative degeneration resulting in mono- and diamino Fe(II) complexes, which exert cytotoxicity effects [140, 141]. The pronounced antineoplastic efficacy of these ligands has been widely attributed to their inhibition on the mammalian enzyme RNR. The ability to inhibit RNR is of particular importance, since the activity of RNR is directly linked with the de novo synthesis of deoxyribonucleotides required for DNA replication and repair. Recently, the mechanisms of action of DpT and BpT analogs, which include alterations in the expression of key regulatory molecules as well as the generation of redox active Fe complexes, were discovered and are important for anticancer activity, resulting in oxidative damage and the inhibition of RNR [142, 143]. Apart from being RNR inhibitors, thiosemicarbazones are typically excellent chelators of transition metals such as Fe, Cu, Zn, Pt, Pd, Ni, Co, etc. [100]. This means that besides RNR activity, thiosemicarbazones can also interact with other targets with other types of mechanism, e.g. redox activity. Indeed

Moorthy et al.

some reports have shown that some thiosemicarbazones inhibit topoisomerase II, demonstrating that this class of agents has multiple molecular targets and acts by various mechanisms. 2-(Quinolin-2-yl-methylene)hydrazinecarbothioamide developed by Huang et al. showed potent antiproliferative activity against various human and mice cancer cells [144]. The mechanistic studies carried out by this research group revealed that this compound is not only an iron chelator, but also a topoisomerase II catalytic inhibitor [144]. The inhibitory effect on topoisomerase II is due to direct interaction with the ATPase domain of topoisomerase II that leads to the blockade of ATP hydrolysis, which is confirmed by molecular docking and competitive inhibitory assay [144]. The iron chelator Dp44mT was reported recently as a Topo II poison, but has a different mechanism of action [42, 144]. The ability of thiosemicarbazones with specific metal chelation is also an attractive strategy in developing anticancer drugs because of the high requirement of neoplastic cells for essential metals needed in growth and proliferation. Bis(thiosemicarbazones) can act as tetradentate ligands for Cu(II) and the stable, neutral complex formed (bis(thiosemicarbazonato)copper(II) complex) is used to coordinate copper radioisotopes for application in diagnostic and therapeutic radiopharmaceuticals. A Cu-complex with stilbene functional group binds to amyloid-beta plaques and this complex radiolabeled with positron emitting Cu-64 radiopharmaceutical, assists the non-invasive diagnosis of Alzheimer's disease by positron emission tomography [145148]. A patent report by Tofilon et al. showed that simultaneous and sequential administration of a radiosensitizing dose of 2-carboxyaldehyde pyridine thiosemicarbazone with ionizing radiations, provided RNR inhibitory activities and DNA synthesis blocking action in cancer patients [149]. Danter and coworkers performed several studies on different thiosemicarbazone and/or semicarbazones for treating cancer (small cell lung cancer, hormone resistant breast cancer, hormone resistant prostate cancer, acute leukemia, colorectal cancer or melonama) and the thiosemicarbazones are characterized by overexpression of RAS, EGFR (epidermal growth factor receptor) mutation, and/or overexpression of AKT2 [150, 151]. Sustained or controlled delivery of a combination of thiosemicarbazones or semicarbazones or their salts with a carrier or excipient (pharmaceutically acceptable) was patented for the treatment of inflammatory and painful febrile conditions in human and animals [79]. Asymmetrical bis (thiosemicarbazones) developed by Donnelly and Paterson, revealed that this important intermediate can be used to develop useful compounds to treat proliferating diseases [152]. Some heteroaryl thiourea derivatives with cyclic ring system reported by Yen et al., have RNR inhibitory activity by binding to RRM2. These compounds have been used to treat various conditions associated with the said protein (RRM2) expression (cancer, mitochondrial diseases, degenerative diseases) [153]. Another development in the thiosemicarbazones described that novel heteroaryl-N-aryl thiosemicarbazones can be used in pest control, which was evaluated


through oral administration or topical application for endoand ectoparasitic infections [154]. In spite of the advances in this field and the potential of thiosemicarbazones derivatives, it must not be forgotten that thiosemicarbazones, like any anticancer drug, will affect both normal and neoplastic cells. This means that in spite of the specificity observed among these molecules, further studies are essential to examine the selectivity of these chelators against tumor cells as compared to their normal counterparts. In addition, there are still many details in their mechanism of action that escape our comprehension and many phenomena are observed that cannot be explained with our present knowledge. This means that this field of research must continue in order to gather a better understanding of their mode of action. However, taking into account the knowledge obtained so far and the potential of thiosemicarbazones for the treatment of neoplasia, the new developments in this field will undoubtedly lead to a more rational and even more effective and selective design of new thiosemicarbazones.

Recent Patents on Anti-Cancer Drug Discovery, 2013, Vol. 8, No. 2 [12] [13]

[14]

[15]

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CONFLICT OF INTEREST

[19]

The authors confirm that there is no conflict of interest concerning the contents of this paper.

[20]

ACKNOWLEDGEMENTS

[21]

N.S.H.N.M. gratefully acknowledges the Fundação para a Ciência e Tecnologia (FCT), Portugal for a Postdoctoral Grant (SFRH/BPD/44469/2008).

[22]

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