A QSAR study on the cytotoxicity of podophyllotoxin analogues against various cancer cell lines.

The powerful inhibitory activity of podophyllotoxin (a natural product) on cell growth led to the development of clinically useful anticancer agents such as etoposide, teniposide, and etopophos. Although, these podophyllotoxin derivatives show good clinical effects against various cancers, its use often results in various undesired side effects, drug resistance, and cytotoxicity towards the normal cells. In order to overcome these limitations, it is essential to search new podophyllotoxin analogues with improved anticancer activity and fewer side effects to gain the maximum benefits for the cancer patients. With this purpose, the cytotoxicity data of two series of podophyllotoxin derivatives against four different cancer cell lines was used to develop 4 QSAR models. Hydrophobic property of the molecules was found one of the most important determining factors for their activity. The developed QSAR models showed a good correlative and predictive abilities having r(2) = 0.960 to 0.836 and q(2) = 0.911 to 0.705. On the basis of QSAR 1, two compounds (10-10 and 10-11) are suggested as potential synthetic targets. Statistical diagnostics and internal validation (cross validation and Y-randomization) tests have validated all the QSAR models. These QSAR models could be useful in the rational design of potential drug molecules with an enhanced inhibitory potency.

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.

Taxane analogues against lung cancer: a quantitative structure-activity relationship study.

Lung cancer is the second most common cancer in both men (after prostate cancer) and women (after breast cancer). The microtubule-stabilizing taxane such as docetaxel is the only agent currently approved for both first- and second-line treatment of advanced non-small cell lung cancer. Although docetaxel has made significant progress in the treatment of lung cancers either using alone or in combination with various novel targeted agents, its use often results in various undesired side-effects. These limitations have led to the search for new taxane derivatives with fewer side-effects, superior pharmacological properties, and improved anticancer activity to maximize the induced benefits for lung cancer patients. Herein, four series of taxane derivatives were used to correlate their inhibitory activities against lung cancer cells with hydrophobic and steric descriptors to gain a better understanding of their chemical-biological interactions. A parabolic correlation with MR(Y) is the most encouraging example, in which the optimum value of this parameter is well defined. On the basis of this quantitative structure-activity relationship model, six compounds (3-23 to 3-28) are suggested as potential synthetic targets. Internal (cross-validation (q(2)), quality factor (Q), Fischer statistics (F ) and Y-randomization) and external validation tests have validated all the quantitative structure-activity relationship models.

Overcoming tumor drug resistance with C2-modified 10-deacetyl-7-propionyl cephalomannines: a QSAR study.

The microtubule-stabilizing taxanes such as paclitaxel and docetaxel are the two most important anticancer drugs currently used in clinics for the treatment of various types of cancers. However, the major common drawbacks of these two drugs are drug resistance, neurotoxicity, substrate for drug transporter P-gp, cross-resistance with other chemotherapeutic agents, low oral bioavailability, and no penetration in the blood-brain barrier (BBB). These limitations have led to the search for new taxane derivatives with improved biological activity. In the present paper, we discuss the quantitative structure-activity relationship (QSAR) studies on a series of C2-modified 10-deacetyl-7-propionyl cephalomannines (IV) with respect to their binding affinities toward beta-tubulin and cytotoxic activities against both drug-sensitive and drug-resistant tumor cells, in which resistance is mediated through either P-gp overexpression or beta-tubulin mutation mechanisms, by the formulation of five QSARs. Hydrophobicity and molar refractivity of the substituents (pi(X) and MR(X)) are found to be the most important determinants for the activity. Parabolic correlations in terms of MR(X) (eqs 2 and 4 ) are encouraging examples in which the optimum values of MR(X) are well-defined. We believe that these two QSAR models may prove to be adequate predictive models that can help to provide guidance in design and synthesis, and subsequently yield very specific cephalomannine derivatives (IV) that may have high biological activities. On the basis of these two QSAR models, 10 cephalomannine analogues (IV-21 to IV-30) are suggested as potential synthetic targets. Internal (cross-validation (q(2)), quality factor (Q), Fischer statistics (F), and Y-randomization) 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.

A QSAR study for the cytotoxic activities of taxoids against macrophage (MPhi)-like cells.

A series of taxoids (modified at the C-3'N position) have been used for the development of two QSAR models for their cytotoxic activities against macrophage (MPhi)-like cells J774.1 and J7.DEF3. QSAR results suggest that hydrophobic and steric features influence the inhibitory activity in a linear model. The ClogP values were not great enough to establish the upper limit of the inhibition. Internal [cross-validation, quality factor (Q), Fischer statistics (F), Y-randomization, and lack of overfitting tests] and external validation tests have validated both the QSAR models.

Combating the threat of anthrax: a quantitative structure-activity relationship approach.

Bacterial agents or products more likely to be used as biological weapons of mass destruction are Bacillus anthracis, Francisella tularensis, Yersinia pestis, and the neurotoxin of Clostridium botulinum. Anthrax is an acute infectious disease with a high mortality rate caused by Bacillus anthracis, reinforcing the need for better adjunctive therapy and prevention strategies. In this paper, we developed 7 QSAR models on penicillin-based inhibitors of the class A and B beta-lactamases from B. anthracis and inhibitors of anthrax lethal factor to understand the chemical-biological interactions. Hydrophobic and steric factors are found to be the most important determinants of the activity. Internal (cross-validation ( q (2)), quality factor ( Q), Fischer statistics ( F), and Y-randomization) and external validation tests have validated all the QSAR models.

Understanding tubulin/microtubule-taxane interactions: a quantitative structure-activity relationship study.

For years, the microtubule-stabilizing agents paclitaxel and docetaxel (progenitors of the family of taxanes) have been the most successful anticancer drugs currently used in clinics. However, both drugs are associated with notorious side effects, drug resistance, and cross resistance with other chemotherapeutic agents. These limitations have led to the search for new drugs with improved biological activity. In the present paper, we discuss the interaction of taxanes with the tubulin/microtubule system by the formulation of 6 QSARs. Hydrophobicity of the substituents (pi) is found to be one of the most important determinants of the activity followed by steric parameters. Parabolic correlations (eqs 3 and 7) with B5 and pi are the most encouraging examples, where the optimum values of these parameters are well defined. We believe that these two QSARs may prove to be adequate predictive models that can help to provide guidance in design/synthesis and subsequently yield very specific compounds (IV and VIII) that may have high biological activities. On the basis of these two QSARs 3 and 7, 18 compounds (IV-12- IV-22 and VIII-16- VIII-22) are suggested as potential synthetic targets. Cross-validation, quality factor (Q), Fischer statistics (F), and Y-randomization tests have validated all the QSAR models.

Taxane analogues against breast cancer: a quantitative structure-activity relationship study.

Breast cancer is the second leading cause of cancer death among women in the United States. Two taxane analogues, taxol and taxotere, are the most important antimitotic drugs currently in clinical use for the treatment of breast cancers. However, recent reports have indicated that the use of these drugs often results in various undesired side effects as well as multi-drug resistance. These limitations have led to the development of new taxane derivatives with fewer side effects, superior pharmacological properties, and improved anticancer activity to maximize the induced benefits for breast cancer patients. Herein, four series of taxane derivatives were used to correlate their inhibitory activities against breast cancer cells with their hydrophobic and steric properties in order to understand their chemical-biological interactions. The resulting QSARs show that the inhibitory activities of taxane analogues against breast cancers are mainly dependent either on their hydrophobicity or the hydrophobic/molar refractivity descriptor of their substituents. A parabolic correlation with MR(Y) is the most encouraging example, in which the optimum value of this parameter is well defined. We believe this correlation may prove to be an adequate predictive model that can help provide guidance in design and synthesis and subsequently yield highly specific compounds that may have high anti-breast-cancer activity with fewer side effects and superior pharmacological properties. On the basis of this QSAR model, five compounds are suggested as potential synthetic targets. Internal (cross-validation (LOO-q(2) and LMO-q(2)), quality factor (Q), Fischer statistics (F), and Y-randomization) and external validation tests have validated all the QSAR models.

Investigation of DNA-binding properties of organic molecules using quantitative structure-activity relationship (QSAR) models.

Due to the great potential of DNA as a receptor, many classes of synthetic and naturally occurring molecules exert their anticancer activities through DNA-binding. In the field of antitumor DNA-binding agents, a number of acridine and anthracycline derivatives are in the market as chemotherapeutic agents. However, the clinical application of such classes of compounds has encountered problems such as multi-drug resistance and secondary and/or collateral effects. Thus, there has been increasing interest in discovering and developing small molecules that are capable of DNA-binding, which will be expected to be used either in place of or in conjunction with, the existing compounds. The interest in the application of the QSAR paradigm has steadily increased in recent decades and we hope it may be useful in the design and development of DNA-binding molecules as new anticancer agents. In the present review, an attempt has been made to understand the DNA-binding properties of different compound series and discussed using 27 QSAR models, which reveal a number of interesting points. The most important determinants for the activity in these models are Hammett electronic (sigma and sigma+), hydrophobic, molar refractivity, and Sterimol width parameters.

20-(S)-camptothecin analogues as DNA topoisomerase I inhibitors: a QSAR study.

The interest in the application of the quantitative structure-activity relationships (QSAR) has steadily increased in recent decades because it has repeatedly proven itself to be a low-cost, high-return investment. Potential use of QSAR models for screening of chemical databases or virtual libraries before their synthesis appears equally attractive to chemical manufacturers, pharmaceutical companies, and government agencies. We hope it may also be useful in the design and development of new camptothecin derivatives as DNA topoisomerase I (topo I) inhibitors. In this paper, two series of camptothecin derivatives were undertaken to correlate DNA topo I inhibition with their hydrophobic and steric properties, to understand their chemical-biological interactions. The resulting QSAR have shown that the inhibitory activity of camptothecin analogues 4 toward DNA topo I is mainly dependent on their hydrophobic and steric descriptors, whereas the same activity of 10,11-methylenedioxy- camptothecin analogues 5 is largely dependent on their hydrophobicity at position-7. Using internal [cross-validation, quality factor (Q), Fischer statistics (F), and Y-randomization tests] and external validation tests both of these QSAR models have been validated. Both series of these camptothecin derivatives are also filtered by Lipinski's rule of five to check their oral bioavailability. On the basis of these QSAR models, five compounds (4-35, 4-36, 5-20, 5-21, and 5-22) have been predicted that may be the next synthetic target. These molecules also fulfill the conditions of Lipinski's rule of five.

Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs.

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. They are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions. MMPs are excreted by a variety of connective tissue and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed by other proteolytic enzymes (such as serine proteases, furin, plasmin, and others) to generate the active forms. Matrix metalloproteinases are considered as promising targets for the treatment of cancer due to their strong involvement in malignant pathologies. Clinical/preclinical studies on MMP inhibition in tumor models brought positive results raising the idea that the development of strategies to inhibit MMPs may be proved to be a powerful tool to fight against cancer. However, the presence of an inherent flexibility in the MMP active-site limits dramatically the accurate modeling of MMP-inhibitor complexes. The interest in the application of quantitative structure-activity relationships (QSARs) has steadily increased in recent decades and we hope it may be useful in elucidating the mechanisms of chemical-biological interactions for this enzyme. In the present review, an attempt has been made to explore the in-depth knowledge from the classification of this enzyme to the clinical trials of their inhibitors. A total number of 92 QSAR models (44 published and 48 new formulated QSAR models) have also been presented to understand the chemical-biological interactions. QSAR results on the inhibition of various compound series against MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 reveal a number of interesting points. The most important of these are hydrophobicity and molar refractivity, which are the most important determinants of the activity.

Comparative QSAR studies on PAMPA/modified PAMPA for high throughput profiling of drug absorption potential with respect to Caco-2 cells and human intestinal absorption.

Despite the dramatic increase in speed of synthesis and biological evaluation of new chemical entities, the number of compounds that survive the rigorous processes associated with drug development is low. Thus, an increased emphasis on thorough ADMET (absorption, distribution, metabolism, excretion and toxicity) studies based on in vitro and in silico approaches allows for early evaluation of new drugs in the development phase. Artificial membrane permeability measurements afford a high throughput, relatively low cost but labor intensive alternative for in vitro determination of drug absorption potential; parallel artificial membrane permeability assays have been extensively utilized to determine drug absorption potentials. The present study provides comparative QSAR analysis on PAMPA/modified PAMPA for high throughput profiling of drugs with respect to Caco-2 cells and human intestinal absorption.

Understanding human rhinovirus infections in terms of QSAR.

The human rhinoviruses (HRVs) are the single most important cause of common colds. The widespread nature of this affliction, the economic consequences, and the well-known impracticality of vaccine development due to the large number of HRV serotypes (>100) have justified the search for chemotherapeutic agents. The interest in the application of quantitative structure-activity relationships has steadily increased in recent decades and we hope it may be useful in the search for anti-HRV agents. In the present paper, we have discussed the inhibition of various six compound series against HRV-1A, -1B, -2, -9, -14, -21, -22, -25, -64, and -89 by the formulation of a total number of 14 QSAR. Hydrophobicity is found to be one of the most important determinants of activity. Parabolic correlation with the hydrophobic parameter (Eq. ) is an encouraging example, where the optimal hydrophobicity is well defined. We believe that this may be the predictive model to narrow the synthetic challenges in order to yield very specific HRV-2 inhibitors. On the basis of this model, we have predicted eleven compounds (I-1 to I-11) that may be the next synthetic target. The proposed molecules (I-1 to I-11) also fulfill the conditions of Lipinski's "rule of five".

Cytotoxicity of organic compounds against ovarian cancer cells: a quantitative structure-activity relationship study.

The interest in the application of structure-activity relationships has steadily increased in recent decades. In the present paper, we have discussed the cytotoxicity of various sets of organic compounds against ovarian cancer cells by the formulation of a total number of 11 QSARs. Hydrophobicity is found to be one of the most important determinants of activity followed by steric parameters. Parabolic correlation with hydrophobicity is an encouraging example, where the optimal hydrophobicity is well-defined. We believe that this may be the predictive model to narrow the synthetic challenges in order to yield very specific OVCAR-3 inhibitors. On the basis of this model, we can predict three compounds that may be the next synthetic target. Cross-validation and Y-randomization tests were used to validate all the QSAR models.

Utility of the mouse dermal promotion assay in comparing the tumorigenic potential of cigarette mainstream smoke.

The International Agency for Research on Cancer (IARC) has classified a number of the chemical constituents reported in cigarette mainstream smoke (MS) as carcinogens. In the international literature, 81 IARC classified carcinogens have been reported historically in MS. Cigarette smoke is a complex aerosol of minute liquid droplets (termed the particulate phase) suspended within a mixture of gases (CO(2), CO, NO(x), etc.) and semi-volatile compounds. The gases and semi-volatiles are termed the vapor phase. Due to early difficulties in inducing carcinomas in laboratory animals following inhalation exposure to MS, the mouse dermal promotion assay became the standard method of comparing the tumorigenic potential of cigarette smoke condensates (the particulate phase of MS nearly devoid of MS gases and having a significant reduction of the semi-volatile components of the vapor phase). Of the 81 IARC carcinogens reported in MS, 48 are found exclusively in the particulate phase, 29 in the vapor phase only, and four IARC carcinogens in both phases. A general comparison of the quantity and potency of the individual carcinogenic constituents of the MS vapor and particulate phases illustrates that the potential carcinogenic contribution from the vapor phase might be significant. Therefore, the mouse dermal promotion assay may not be a sensitive comparator of the tumorigenic potential of different MSs displaying a diversity of vapor phase components. However, when used in a weight-of-the-evidence approach that includes smoke chemistry, in vitro studies using whole smoke and human exposure studies evaluating both vapor and particulate phase smoke constituents, the mouse dermal promotion assay remains an important risk assessment tool as the only test that reproducibly measures the tumorigenic potential of cigarette smoke condensate.