Rajeshwar P. Verma

Camptothecins: a SAR/QSAR study.

Camptothecin (CPT, I), a unique pentacyclic quinoline alkaloid originally isolated from a native tree of Tibet and China called Camptotheca acuminata in latin and Xi Shu in Chinese, is one of the prominent lead compounds in anticancer drug development.1-3 It has been identified from the early assessments that the importance of 20S chiral carbon of CPT for their activity and also pointed out a dynamic equilibrium between the close-ring lactone and open-ring carboxylic acid forms at physiological pH. Due to the extremely poor solubility of CPT in water, clinical trials were initiated using its water-soluble sodium salt (II; Figure 1). The results were disappointing: biological activity was weak relative to xenograph models and unexpected side effects including hemorrhagic cystitis and myelotoxicity, which resulted in suspension of the trials.4,5 Later on, it was established that the R-hydroxy lactone ring moiety must be intact for antitumor activity and that this ring was being opened in the preparation of the sodium salt.6 In a conformational analysis, torsional parameters for the MM3(96) force field were obtained by Carrigan et al.7 for the R-hydroxy lactone and CPT using ab initio calculations on representative compounds containing the critical dihedral angles. MM3(96) predicts two distinct “boat-like” conformations for the R-hydroxy lactone moiety. The low-energy lactone conformation predicted by MM3(96) is in good agreement with X-ray crystal structures of CPT iodoacetate and 7-ethyl-10-(4-piperidino)piperidinylcarbonyloxy CPT HCl as well as the ab initio structure of a CPT-like R-hydroxy lactone. Nearly 20 years later, the discovery that the primary cellular target of CPT is DNA topoisomerase I (topo I) was the breakthrough that renewed interest in this agent and led to synthesizing more water-soluble analogues.8-10 Two of them, topotecan (Hycamptin, III) for the clinical treatment of the ovarian and small-cell lung cancers,11-14 and irinotecan (Camptosar or CPT-11, IV)15,16 for the metastatic colorectal cancers have already gained approval by the Food and Drug Administration (FDA) of the U.S.A.17,18 Irinotecan is a prodrug that is converted into their active metabolic form 10-hydroxy-7-ethylcamptothecin (SN-38, V; Figure 2). These two drugs (topotecan and irinotecan) and other derivatives of CPT have become a part of the multimillion dollar industry that is dedicated to finding better chemotherapeutic agents with excellent antitumor activity and less normal tissue toxicity. To achieve this goal, it is necessary to understand the details about the mechanisms of action, the targets of these drugs, and the cellular response to the drugs. Human topoisomerase I (topo I) relaxes superhelical tension associated with DNA replication, transcription and recombination by reversibly nicking one strand of duplex DNA and forming a covalent 3′-phosphotyrosine linkage. This enzyme is the sole target of the CPT family of anticancer compounds, which acts by stabilizing the covalent protein-DNA complex and enhancing apoptosis through blocking the advancement of replication forks. Once the CPT molecule has intercalated into the topo I-DNA cleavable complex, the collision between the complex and the replication fork during S-phase is thought to result in DNA double strand breaks (DSBs) that eventually lead to cell death.18,19 It has also been suggested that topo I cleaves DNA at multiple sites. The highest efficient sites exhibit significant sequence homology. Approximately 90% of topo I site have a tyrosine residue at position-1. However, sites of cleavage stabilized by CPT exhibit a strong preference for guanine at +1 position, while thymidine remains the preferred nucleobase at the -1 position.20 The exact mechanism by which CPT stabilizes the DNAtopo I covalent binary complex is not fully understood because the drug acts as an uncompetitive inhibitor and binds only the transient binary complex.21 Enzymology studies have revealed that CPT does not interact with topo I alone, nor does it bind to DNA.22 Although it has been reported that topotecan, which should be protonated at physiological pH, does bind to DNA at high concentration.23 Despite the * Phone: (909) 607-4249. Fax: (909) 607-7726. E-mail: rverma@ pomona.edu. Chem. Rev. 2009, 109, 213–235 213

QSAR: then and now.

In this review, the evolution of QSAR is traced from the insightful observations of Crum-Brown and Frazier to Hammetts critical equations and finally Hanschs seminal contributions on hydrophobicity and modelling of biological activity based on extrathermodynamic principles. Todays QSAR models can stand alone, augment other graphical approaches or be examined in tandem with equations of a similar mechanistic genre to truly reveal the power of the paradigm. This review will focus on the three standard classifications routinely used in QSAR analysis electronic, hydrophobic, and steric, as well as topological indices. Electronic parameters will focus on Hammett sigma constants and their numerous variations. Dipole moments, hydrogen bond descriptors and quantum chemical indices as well as applications of their utilization will be described. The hydrophobicity parameter will be examined by tracing its early history, its operational definition and its determination by either experimental methods or computational calculations. Steric parameters, which run the gamut from size to shape, will be described by Tafts, Hancocks, Chartons, Fujitas, Verloops and Simons contributions. Topological effects, delineated by connectivity indices, kappa shape and electrotopological indices of Kier and Hall are also described. Examples of QSAR models incorporating most of these parameters are reviewed. In cases where the 95% confidence intervals of variables are available, they are listed in parentheses. A brief Comparative QSAR analysis of non-nucleoside reverse transcriptase inhibitors (NNRTIs) is outlined and various models obtained by different groups examining 4, 5, 6, 7-tetrahydro-5-methylimidazo [4, 5,1-j,k][1,4] benzodiazepin-2(1H)-ones (TIBO) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) derivatives are compared for mechanistic insight that could be useful in the process of inhibitor design.

QSAR of Cytochrome P450

The cytochrome P450 class of enzymes is an extremely important and complex group. It has a significant place in ADME (adsorption, distribution, metabolism, elimination) that those developing new drugs must be concerned with. While there are various ways in which organic compounds can undergo metabolic attack, P450 is probably the most important. Recently, Lewis (2000) reviewed his extensive studies on P450 and efforts to use QSAR to gain a deeper understanding on this important class of enzymes. We have also been interested in the QSAR of P450 enzymes, but much has appeared since our last review (Hansch and Zhang, 1993).

Novel peptidomimetic compounds containing redox active chalcogens and quinones as potential anticancer agents.

Many types of cancer cells are associated with a disturbed intracellular redox balance and oxidative stress (OS). Among the various agents employed to modulate the intracellular redox state of cells, certain redox catalysts containing quinone and chalcogen moieties have shown considerable promise. Passerini multicomponent reaction has been developed for the synthesis of agents combining two, three or even four redox centers in one molecule in a good yield. When incubated with cancer cells these agents inhibited cell proliferation and induced apoptotic cell death. Interestingly, some of these redox active compounds exhibited quite low toxicity with normal cells. The cause was obviously OS, which was reflected by significant decrease in reduced glutathione, subsequently cell cycle arrest and induction of apoptosis.

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.

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).

QSAR modeling of taxane analogues against colon cancer

Although taxanes such as paclitaxel and docetaxel are the two most important clinically available anticancer drugs for the treatment of various cancers (including colon cancer), the success of these two drugs has been tempered by the development of various unbearable side effects as well as multi-drug resistance. Therefore, it is essential to search new taxane analogues with improved anticancer activity and fewer side effects to gain the maximum benefits for colon cancer patients. In this paper, four series of taxane derivatives were used to correlate their inhibitory activities against colon cancers mainly with the hydrophobic and steric descriptors of their substituents in order to gain a better understanding of their chemical-biological interactions. QSAR results from this paper have suggested that the steric and hydrophobic parameters of the substituents are the two most important determinants for the activities of taxane analogues (under consideration) against colon cancers, with a major contribution coming from the molar refractivity of the substituents. Statistical diagnostics, internal validation, and external validation tests have validated all the QSAR models.

Larvicidal activities of some organotin compounds on mosquito larvae: a QSAR study.

Mosquitoes are not only the cause of nuisance by their bites but also transmit deadly diseases like malaria, filariasis, yellow fever, dengue, and Japanese encephalitis. In this paper, nine QSAR models were developed using different series of organotins with respect to their larvicidal activities against Aedes aegypti and Anopheles stephensi mosquito larvae. Internal [cross-validation (LOO-q(2)), quality factor (Q), Fischer statistics (F), and Y-randomization] and external validation tests have validated all these QSAR models. QSAR results suggest that the two most important determinants for the toxicity are the hydrophobic (pi) and Hammett electronic (sigma(+)) parameters of the substituents, and the kill mechanism is different for these two species of mosquito larvae. On the basis of QSAR (6), nine compounds 4a-4i are suggested as potential synthetic targets.

Toxicology of benzyl alcohols: a QSAR analysis

There is an evidence that benzyl alcohols may exhibit toxicity via a radical mechanism. To test this possibility, we studied the toxicity of para substituted benzyl alcohols on rapidly dividing cancer cells (L1210 leukemia). This system has previously found utility in studying the apparent radical toxicity of a variety of phenols. However, no evidence could be found for an electronic effect and the cellular toxicity was associated primarily with hydrophobicity. Comparison of this quantitative structure-activity relationships (QSAR) with others for the reactions of benzyl alcohols in diverse systems provides insight into mechanisms of action. A QSAR for the interaction of benzyl alcohols with protozoa yields an equation that is dependent on both hydrophobicity and acidity of the OH group versus a mixture of bacteria and fungi, the critical dependence on hydrophobicity prevails with a small dependence on a resonance-stabilized, radical mediated electronic effect. The chloramphenicols provide an instructive example, where the radical mediated electronic effect overshadows the hydrophobic contribution to bacterial toxicity. These various QSAR for benzyl alcohols indicate that mechanisms of growth inhibition in vitro vary depending on cell/organism type, the strength of the bond and lability of the hydrogen, and the strength of the initiating radical reagent.

SYNTHESIS AND ANTI-INFLAMMATORY ACTIVITY EVALUATION OF SOME ACRIDINYL AMINO ANTIPYRINE, ACRIDINYL AMINO ANTHRAQUINONE, ACRIDINO THIOUREA AND THIAZOLINO THIOUREA DERIVATIVES

Abstract 9- Chloro - 2(substituted) - acridines (I) on condensation with 4 - amino antipyrine, I-amino anthraquinone and 2 - amino anthraquinone gave corresponding condensed products II, III and IV. Phenyl isothiocyanate reacts with 9 - amino - 2 or 4 (substituted)-acridines (V) and iminothiazolines (VII) to give corresponding N-phenyl -N′- substituted thioureas VI and VIII in good yield. Anti-inflammatory activity screening for IIa, b, In, IV, VIb and VIIIa - I was carried out at 100 mg/kg p.o. and compounds IV, VIIIa, VIIIb and VIIIg-k showed 12, 12, 14, 18, 7, 23, 13 and 18% activity whereas all others were found to be inactive. Analgesic activity screening for IIb, III and IV was carried out at 100mg/kg p.o. Only compound III showed 25% activity whereas IIb and IV were found to be inactive.