An in vitro comparative assessment with a series of new triphenyltin(IV) 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates endowed with anticancer activities: structural modifications, analysis of efficacy and cytotoxicity involving human tumor cell lines.

Four new triphenyltin(IV) complexes of composition Ph(3)SnLH (where LH=2-/4-[(E)-2-(aryl)-1-diazenyl]benzoate) (1-4) were synthesized and characterized by spectroscopic (((1))H, ((13))C and ((119))Sn NMR, IR, ((119))Sn Mössbauer) techniques in combination with elemental analysis. The ((119))Sn NMR spectroscopic data indicate a tetrahedral coordination geometry in non-coordinating solvents. The crystal structures of three complexes, Ph(3)SnL((1))H (1), Ph(3)SnL((3))H (3), Ph(3)SnL((4))H (4), were determined. All display an essentially tetrahedral geometry with angles ranging from 93.50(8) to 124.5(2)°; ((119))Sn Mössbauer spectral data support this assignment. The cytotoxicity studies were performed with complexes 1-4, along with a previously reported complex (5) in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with the results from other related triphenyltin(IV) complexes (6-7) and tributyltin(IV) complexes (8-11) having 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates framework. In general, the complexes exhibit stronger cytotoxic activity. The results obtained for 1-3 are also comparable to those of its o-analogs i.e. 4-7, except 5, but the advantage is the former set of complexes demonstrated two folds more cytotoxic activity for the cell line MCF-7 with ID(50) values in the range 41-53 ng/ml. Undoubtedly, the cytotoxic results of complexes 1-3 are far superior to CDDP, 5-FU and ETO, and related tributyltin(IV) complexes 8-11. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of triphenyltin(IV) complexes 1-7 and tributyltin(IV) complexes 8-11 is also discussed against a panel of human tumor cell lines.

Synthesis, structural characterization and in vitro biological screening of some homoleptic copper(II) complexes with substituted guanidines.

A series of homoleptic copper(II) complexes (1a-8a) with N,N',N″-trisubstituted guanidines, [Cu(II){PhCONHC(NHR)NPh}(2)] (where R = phenyl (1a), n-butyl (2a), sec-butyl (3a), cyclohexyl (4a), 1-naphthyl (5a), 2,4-dichlorophenyl (6a), 3,4-dichlorophenyl (7a), and 3,5-dichlorophenyl (8a)) have been synthesized and characterized by elemental analyses, FT-IR, UV-visible, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction analysis. The X-ray crystal structures revealed that the complexes 2a and 4a are mononuclear in the solid state and that the geometry around the copper atom is nearly square planar. In both the cases, N,N',N″-trisubstituted guanidine ligands have been coordinated to the Cu(II) through the oxygen and nitrogen atoms. The synthesized guanidines and their complexes were initially screened for their anti-microbial activities, and Brine Shrimps Lethality assay. The complexes were also screened for in vitro cytotoxicity activity in human cell lines carcinomas A498, EVSAT, H226, IGROV, M19, MCF-7 and WIDR. The results show a moderate level of cytotoxicity against these seven human cancer cell lines as compared with standard chemotherapeutic drugs.

Advancement towards tin-based anticancer chemotherapeutics: structural modification and computer modeling approach to drug-enzyme interactions.

Three new triphenyltin(IV) complexes, viz., triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(methoxycarbonyl)phenyl)imino)methyl)phenyl)-diazenyl)benzoate (Ph(3)SnL(2)H: 2), methyl 2-((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate (Ph(3)SnL(3)H: 3), and triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate ((Ph(3)Sn)(2)L(4)H: 4) were synthesized and characterized by spectroscopic ((1)H, (119)Sn NMR and IR) techniques in combination with elemental analysis. The (119)Sn NMR spectral data were recorded in a non-coordinating solvent and indicate tetrahedral coordination geometry in solution. In the solid state, a single-crystal X-ray diffraction analysis of the dinuclear complex (Ph(3)Sn)(2)L(4)H (4) revealed a monocapped tetrahedral coordination geometry with anisobidentate coordination modes of the carboxylate groups with average bond angles around the Sn atoms of 113.5 and 112.2°, respectively. In vitro cytotoxicity studies were performed with all three complexes 2-4, along with a previously reported parent aquatriphenylstannyl complex, 2-((3-formyl-4-hydroxyphenyl)diazenyl)benzoate (Ph(3)SnL(1)H.OH(2) (1)) across a panel of human tumor cell lines, viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with those from related triphenyltin(IV) carboxylates containing (i) imino (11-16) and (ii) diazenyl frameworks (1, 5-10). In general, complexes 2-4 exhibited good cytotoxic activity and among them, compound 4 was found to be the best performer, particularly for EVSA-T and MCF-7 cell lines. Additionally, 4 scored better activity than cisplatin (2-15 folds), 5-fluorouracil and etoposide across a panel of cell lines. Docking studies indicated that the diazenyl and imino nitrogen atoms, and the oxygen atoms of triphenyltin ester, methyl ester and phenolic group play an important role for the complexation of the organotin compounds in the active sites of enzymes such as ribonucleotide reductase (pdb ID: 4R1R), thymidylate synthase (pdb ID: 2G8D), thymidylate phosphorylase (pdb ID: 1BRW) and topoisomerase II (pdb ID: 1QZR).

Dibutyltin(IV) complexes containing arylazobenzoate ligands: chemistry, in vitro cytotoxic effects on human tumor cell lines and mode of interaction with some enzymes.

Dibutyltin(IV) complexes of composition Bu2Sn(LH)2, where LH is a carboxylate residue derived from 2-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L¹H) with water molecule (1), 4-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L²H) (2) and 4-[(E)-(4-hydroxy-5-methylphenyl)diazenyl]benzoate (L³H) (3), were synthesized and characterized by spectroscopic (¹H, ¹³C and ¹¹9Sn NMR, IR, ¹¹9Sn Mössbauer) techniques. A full characterization was accomplished from the crystal structure of complex 1. The molecular structures and geometries of the complexes (1a i.e. 1 without water molecule and 3) were fully optimized using the quantum mechanical method (PM6). Complexes 1 and 3 were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. Compound 3 is found to be four times superior for the A498, EVSA-T and MCF-7 cell lines than CCDP (cisplatin), and four, eight and sixteen times superior for the A498, H226 and MCF-7 cell lines, respectively, compared to ETO (etoposide). The mechanistic role of cytotoxic activity of test compounds is discussed in relation to the theoretical results of docking studies with some key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II associated with the propagation of cancer.

Molecular basis of the interaction of novel tributyltin(IV) 2/4-[(E)-2-(aryl)-1-diazenyl]benzoates endowed with an improved cytotoxic profile: synthesis, structure, biological efficacy and QSAR studies.

A series of tributyltin(IV) complexes based on 2/4-[(E)-2-(aryl)-1-diazenyl]benzoate ligands was synthesized, wherein the position of the carboxylate and aryl substituents (methyl, tert-butyl and hydroxyl) varies. The complexes, Bu(3)SnL(1-4)H (1-4), have been structurally characterized by elemental analysis and IR, NMR ((1)H, (13)C, and (119)Sn) and (119)Sn Mössbauer spectroscopy. All have a tetrahedral geometry in solution and a trigonal bipyramidal geometry in the solid-state, except for Bu(3)SnL(4)H (4) that was ascertained to have tetrahedral coordination by X-ray crystallography. Cytotoxicity studies were carried out on human tumor cell lines A498 (renal cancer), EVSA-T (mammary cancer), H226 (non-small-cell lung cancer), IGROV (ovarian cancer), M19 MEL (melanoma), MCF-7 (mammary cancer) and WIDR (colon cancer). Compared to cisplatin, test compounds 1-4 had remarkably good activity, despite the presence of substantial steric bulk due to Sn-Bu ligands. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of organotin(IV) benzoates, along with some reference drug molecules, is also discussed against a panel of human tumor cell lines. Molecular structures of the tributyltin(IV) complexes (1-4) were fully optimized using the PM6 semi-empirical method and docking studies performed with key enzymes associated with the propagation of cancer, namely ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II. The theoretical results are discussed in relation to the mechanistic role of the cytotoxic active test compounds (1-4).

Triphenyltin(IV) 2-[(E)-2-(aryl)-1-diazenyl]benzoates as anticancer drugs: synthesis, structural characterization, in vitro cytotoxicity and study of its influence towards the mechanistic role of some key enzymes.

Triphenyltin(IV) complexes of composition [Ph(3)SnL(1)H](n) (1) and [Ph(3)SnL(2)H](n) (2) (where L(1)H = 2-[(E)-2-(3-formyl-4-hydroxyphenyl)-1-diazenyl]benzoate and L(2)H = 2-[(E)-2-(4-Hydroxy-5-methylphenyl)-1-diazenyl]benzoate) were synthesized and characterized by spectroscopic ((1)H, (13)C and (119)Sn NMR, IR, (119)Sn Mössbauer) techniques in combination with elemental analysis. The molecular structures and geometries of the complexes (1 and 2) were fully optimized using the quantum mechanical method (PM3). Complexes (1 and 2) were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumour cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The test compounds 1 and 2 exhibit comparable results and both the compounds are found to be far superior to CCDP (cisplatin), 5-FU (5-fluorouracil) and ETO (etoposide) across a panel of cell lines and the activity is more pronounced for the A498 (22 fold) and H226 (33 fold) cell lines compared to CCDP, and A498 (13 fold), H226 (39 fold) and MCF-7 (33 fold) cell lines compared to ETO. The test compounds are even 23 fold more active in magnitude in terms of the ID(50) value at least against the H226 cell lines when compared with MTX (methotrexate). Further, the mechanistic role of cytotoxic activity of test compounds (1 and 2), are discussed in relations to the theoretical results of docking studies with some of the key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II.

In vitro cytotoxic evaluation of novel dichlorodiorgano[N-(2-pyridylmethylene)arylamine]tin(IV) derivatives in human tumor cell lines.

The present report overviews the studies on diorganotin(IV) complexes of N-(2-pyridylmethylene)arylamine, R(2)SnCl(2).L (R = Me (1), Et (2), Bu (3) or Ph (4)) as cytotoxic agents. This family of complexes was designed to include highly electron-donating N;Nchelating ligand to afford octahedral R(2)SnCl(2).L complexes of relatively high hydrolytic stability, with the aim to retain ligand binding throughout the biological activity for achieving controlled processes and allowing mechanistic evaluation. It is observed that the high cytotoxic activity is dependent on the Sn-R groups and Sn-N bond lengths, and which is related to the cytotoxic potential. Complex (2) was found to exhibit stronger cytotoxic activity in vitro particularly for A498 (renal cancer), IGROV (ovarian cancer), MCF-7 (breast cancer), and WIDR (colon cancer) of human tumour cell lines and the results are far superior to standard reference drugs e.g., doxorubicin, cisplatin, 5-fluorouracil, methotrexate, etoposide including paclitaxel. The important insights gained with the diorganotin(IV) compounds in regards to their cytotoxic activity are discussed.

Amino acetate functionalized Schiff base organotin(IV) complexes as anticancer drugs: synthesis, structural characterization, and in vitro cytotoxicity studies.

Potassium 2-{[(2Z)-(3-hydroxy-1-methyl-2-butenylidene)]amino}-4-methyl-pentanoate (L(1)HK) and potassium 2-{[(E)-1-(2-hydroxyphenyl)alkylidene]amino}-4-methyl-pentanoates (L(2)HK-L(3)HK) underwent reactions with Ph(n)SnCl(4-n) (n = 2 and 3) to give the amino acetate functionalized Schiff base organotin(IV) complexes [Ph(3)SnLH](n)(1-3) and [Ph(2)SnL] (4), respectively. These complexes have been characterized by (1)H, (13)C, (119)Sn NMR, IR spectroscopic techniques in combination with elemental analyses. The crystal structures of 1 and 3 were determined. The crystal structures reveal that the complexes exist as polymeric chains in which the L-bridged Sn-atoms adopt a trans-R(3)SnO(2) trigonal bipyramidal configuration with the Ph groups in the equatorial positions and the axial locations occupied by a carboxylate oxygen atom from one carboxylate ligand and the alcoholic or phenolic oxygen atom of the next carboxylate ligand in the chain. The carboxylate ligands coordinate in the zwitterionic form with the alcoholic/phenolic proton moved to the nearby nitrogen atom. The solution structures were predicted by (119)Sn NMR spectroscopy. When these organotin(IV) complexes were tested against A498, EVSA-T, H226, IGROV, M19 MEL, MCF7 and WIDR human tumor cell lines, the average ID(50) values obtained were 55, 80 and 35 ng/ml for triphenyltin(IV) compounds 1-3, respectively. The most cytotoxic triphenyltin(IV) compound in the present report (3) with an average ID(50) value of around 35 ng/ml is found to be more cytotoxic for all the cell lines studied than doxorubicin, cisplatin, 5-fluorouracil and etoposide.

Synthesis, crystal structures, cytotoxicity and qualitative structure-activity relationship (QSAR) of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolinolato}di-n-butyltin(IV) complexes, (n)Bu2Sn(L)2.

A series of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolinolato}di-n-butyltin(IV) complexes has been synthesized and characterized by (1)H-, (13)C-, (119)Sn NMR, ESI-MS (electrospray ionization mass spectrometry), IR and (119m)Sn Mössbauer spectroscopic techniques in combination with elemental analyses. The structures of four di-n-butyltin(IV) complexes, viz., (n)Bu(2)Sn(L(3))(2) (3), (n)Bu(2)Sn(L(4))(2) (4), (n)Bu(2)Sn(L(5))(2) (5) and (n)Bu(2)Sn(L(7))(2).0.5C(6)H(6) (7) (LH=5-[(E)-2-(aryl)-1-diazenyl)quinolin-8-ol) were determined by single crystal X-ray diffraction. In general, the complexes were found to adopt a distorted cis-octahedral arrangement around the tin atom. These complexes retain their solid-state structure in non-coordinating solvent as evidenced by (119)Sn and (13)C NMR spectroscopic results. The in vitro cytotoxicity of di-n-butyltin(IV) complexes (3-8) is reported against seven well characterized human tumour cell lines. The basicity of the two quinolinolato donor N and O atoms of the ligands are discussed in relation to the cytotoxicity data.

Synthesis, characterization, and in vitro cytotoxicity of some gold(I) and trans platinum(II) thionate complexes containing water-soluble PTA and DAPTA ligands. X-ray crystal structures of [Au(SC4H3N2)(PTA)], trans-[Pt(SC4H3N2)2(PTA)2], trans-[Pt(SC5H4N)2(PTA)2], and trans-[Pt(SC5H4N)2(DAPTA)2].

A series of gold(I) and platinum(II) complexes of the type [Au(SR)(P)] and trans-[Pt(SR) 2(P) 2] [SR = 2-thiopyridine (SPy), 2-thiopyrimidine (SPyrim); P = 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA)] were prepared and characterized, and their in vitro cytotoxicities against a panel of seven human cancer cell lines were evaluated. The highly water soluble gold(I) complexes [Au(SR)(P)] [P = PTA and SR = SPy ( 1), SPyrim ( 2); P = DAPTA and SR = SPy ( 3), SPyrim ( 4)] showed low cytotoxicity, while the platinum(II) complexes trans-[Pt(SR) 2(P) 2] [P = PTA and SR = SPyrim ( 5), SPy ( 6); P = DAPTA and SR = SPyrim ( 7), SPy ( 8)] demonstrated potent cytotoxicity for ovarian, colon, renal, and melanoma cancer cell lines on the basis of a comparison with ID 50 values for some established cytotoxic drugs. Single crystals of 2, 5, 6, and 8 suitable for X-ray structural characterization were obtained, and the study revealed the trans configuration for 5, 6, and 8 in their solid states.

Cytotoxicity, qualitative structure-activity relationship (QSAR), and anti-tumor activity of bismuth dithiocarbamate complexes.

Bismuth dithiocarbamate complexes of general formula Bi(S(2)CNR(2))(3) demonstrate potent in vitro cytotoxicity against a panel of seven human cancer cell lines; a structure-activity relationship has been established. Potency exhibited by the R=Et (2) derivative, for example, is unrivalled by standard cancer drugs with the exception of paclitaxel. In vivo studies indicate a significant anti-tumor effect exerted by (2) against both OVCAR-3, an ovarian cancer cell line, and HT-29, a colon carcinoma cell line.

Decitabine: a historical review of the development of an epigenetic drug.

The development of decitabine from its synthesis in 1964 to the submission of a registration file has been described. Although the unique DNA-demethylating capacity of decitabine is known for a long time, its application is under continuing investigation. The use of decitabine in MDS, AML, CML, stem cell transplant, sickle cell anemia and thalassemia looks promising. The epigenetic dose seems lower than the cytotoxic dose. Whereas most drugs have matured after 40 years, decitabine is only at the beginning of a new development phase in epigenesis.

Epigenetic drugs: a longstanding story.

In this chapter, the development of decitabine from its synthesis in 1964 to the submission of a registration file in 2004 is reviewed. The proper application of the unique properties of decitabine took quite some time to elucidate. In addition, the practical handling in the clinic was not easy as the prolonged myelosuppression of decitabine made it difficult to determine the preferred dose and schedule. Laboratory studies on DNA methylation and cell differentiation showed possible applications in solid and hematologic malignancies. However, despite many attempts, results in solid tumors have been disappointing thus far. After thorough investigation, decitabine achieved therapeutic application in myelodysplastic syndrome (MDS), in particular in patients with a poor prognosis. Further indications may include acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), hematopoietic stem cell transplantation, sickle cell anemia, and thalassemia. Whereas most drugs are already at the end of their life cycle after 40 years, decitabine is only at the beginning. Its application will broaden with the increase in knowledge of epigenetic mechanisms and their relationship to drug therapy.

Tridemethylisovelleral, a potent cytotoxic agent.

The synthesis and in vitro cytotoxicity toward various tumor cell lines of (+/-)-tridemethylisovelleral, an analogue of the bioactive fungal sesquiterpene (+)-isovelleral retaining the bicyclo[4,1,0]hept-2-en-1,2-dicarbaldehyde system but lacking the three methyl groups, is reported. The cytotoxicity of tridemethylisovelleral toward several tumor cell lines was found to be comparable with those of established antitumor drugs, and significantly higher than that of isovelleral.

Structure-dependent in vitro cytotoxicity of the isomeric complexes [Ru(L)2Cl2] (L= o-tolylazopyridine and 4-methyl-2-phenylazopyridine) in comparison to [Ru(azpy)2Cl2].

The dichlorobis(2-phenylazopyridine)ruthenium(II) complexes, [Ru(azpy)(2)Cl(2)], are under renewed investigation due to their potential anticancer activity. The three most common isomers alpha-, beta- and gamma-[RuL(2)Cl(2)] with L= o-tolylazopyridine (tazpy) and 4-methyl-2-phenylazopyridine (mazpy) (alpha indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual cis, trans, cis positions, beta indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual cis, cis, cis positions, and gamma indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual trans, cis, cis positions) are synthesized and characterized by NMR spectroscopy. The molecular structures of gamma-[Ru(tazpy)(2)Cl(2)] and alpha-[Ru(mazpy)(2)Cl(2)] are determined by X-ray diffraction analysis. The IC(50) values of the geometrically isomeric [Ru(tazpy)(2)Cl(2)] and [Ru(mazpy)(2)Cl(2)] complexes compared with those of the parent [Ru(azpy)(2)Cl(2)] complexes are determined in a series of human tumour cell lines (MCF-7, EVSA-T, WIDR, IGROV, M19, A498 and H266). These data unambiguously show for all complexes the following trend: the alpha isomer shows a very high cytotoxicity, whereas the beta isomer is a factor 10 less cytotoxic. The gamma isomers of [Ru(tazpy)(2)Cl(2)] and [Ru(mazpy)(2)Cl(2)] display a very high cytotoxicity comparable to that of the gamma isomer of the parent compound [Ru(azpy)(2)Cl(2)] and to that of the alpha isomer. These biological data are of the utmost importance for a better understanding of the structure-activity relationships for the isomeric [RuL(2)Cl(2)] complexes.

Cytotoxicity profiles for a series of triorganophosphinegold(I) dithiocarbamates and triorganophosphinegold(I) xanthates.

A series of triorganophosphinegold(1) dithiocarbamate (R(3)PAuS(2)CNR'(2)) and xanthate (R(3)PAuS(2)COR') complexes have been prepared and characterised spectroscopically. Based on crystallographic evidence, the molecules feature linear gold(1) geometries defined by sulphur and phosphorus donors. The complexes, along with a series of known anti-cancer agents, have been screened against a panel of seven human cancer cell lines. Uniformly, the dithiocarbamate derivatives are more active than their xanthate counterparts, with the most active complex being Et(3)PAu(S(2)CNEt(2)), and are more active than cisplatin in all cell lines screened but, not as potent as taxol.

Cytotoxicity of Triorganophosphinegold(I) n-Mercaptobenzoates, n = 2, 3 and 4.

The results of cytotoxicity trials against a panel of seven human cell lines for a series of triorganophosphinegold(I) 3- and 4-mercaptobenzoates are reported. While the new compounds show moderate to high toxicity, their potencies are inferior to those reported previously for their isomeric 2- mercaptobenzoate derivatives. The results therefore suggest a structure-activity relationship in that the 2-isomeric species are more active, particularly against the non-small cell lung cancer and renal cancer cell lines, results that may indicate some selectivity in their cytotoxic profile.

3-D QSAR studies on new dibenzyltin(IV) anticancer agents by comparative molecular field analysis (CoMFA).

Dibenzyltin(IV)dichloride and dibenzyltin(IV)diisothiocyanate derivatives with N,S-donor ligands show significant cytotoxic activities against human cancer cell lines, and are well compared to analogous dialkyltin(IV) derivatives. CoMFA models were generated for the first time for these organotin derivatives using the cytotoxic activities (against two human tumor cell lines, MCF-7, a mammary carcinoma and WiDr, a colon carcinoma) of 21 complexes. High r(2) and r(2)(cv) values for both CoMFA models indicate good predictive power for the models.