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Rajni Garg

Publications and source records attributed to Rajni Garg.

14 recordsLinked to original sources
PubMed2006

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.

Animals↗
PubMed2005

Hydrophobicity in the design of P2/P2' tetrahydropyrimidinone HIV protease inhibitors.

As part of an ongoing effort in understanding the role of hydrophobicity in the design of nonpeptidic HIV protease inhibitors, the QSAR study on P2/P2' tetrahydropyrimidinone is presented in this report. Our results suggest that the balance of hydrophobicity and a volume- dependent polarizability term plays a key role in the inhibition of the viral protease by these inhibitors. The size of the substituent of ligands at particular positions that induce steric fit is crucial. The role of hydrophobicity in the design of tetrahydropyrimidinone is discussed. It has been found that a sufficient spread in the data is required to observe the optimum value of ClogP for these inhibitors.

Drug Design↗
PubMed2005

From SAR to comparative QSAR: role of hydrophobicity in the design of 4-hydroxy-5,6-dihydropyran-2-ones HIV-1 protease inhibitors.

Role of hydrophobicity in the design of 4-hydroxy-5,6-dihydropyran-2-ones-a new class of emerging HIV-1 protease inhibitors (HIV-PI) was investigated by using comparative QSAR. These studies show that most of the data points in the individual dataset studied fall either on positive or negative side of the optimum value of ClogP. This is why, we observe either a positive or negative ClogP term in the QSAR. To observe the optimum value of ClogP for these inhibitors, a sufficient spread in the data is required. It is hoped that the results of this study would help in optimizing substituents for better binding at enzyme pockets and guide in the design of more effective HIV-PI of this class.

Anti-HIV Agents↗
PubMed2004

A mechanistic study of 3-aminoindazole cyclic urea HIV-1 protease inhibitors using comparative QSAR.

Comparative QSAR studies on P2/P2' and P1/P1' substituted symmetrical and nonsymmetrical 3-aminoindazole cyclic urea HIV-1 protease inhibitors were performed. The protease inhibitory activity of these compounds was found to decrease with larger and more hydrophobic molecules, whereas the antiviral potency and translation across the cell membrane increases with increase in hydrophobicity and size. These results provide mechanistic insight about the mode of interaction of these compounds with HIV-1 protease receptor and would help in further improving the biological activity.

HIV Protease↗
PubMed2004

Percutaneous penetration enhancers in cigarette mainstream smoke.

Percutaneous penetration enhancers (PPEs) are chemicals used to enhance the transdermal delivery of drugs. Fifty-eight of the approximately 150 PPEs used for the transdermal delivery of drugs have been reported in cigarette mainstream smoke (MS). MS 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 many of the semi-volatiles are termed the vapor phase. Twenty-nine of the 58 PPEs have been identified in MS vapor phase, 15 in the particulate phase and 14 in both the vapor and particulate phases. There is a tendency for MS PPEs to be hydrophobic, with 40 of the 58 compounds (69%) being either hydrophobic or strongly hydrophobic, and only 24% being hydrophilic. Many of the 4800 known constituents of MS are hydrophilic and would not be expected to readily cross cell membranes or penetrate tissue when delivered as single compounds. The in vivo effect on biological activity of the juxtaposition within the cigarette smoke aerosol of the large number of hydrophilic constituents with the 58 PPEs is currently unknown. As an initial step in understanding this potential complex interaction, the 58 PPEs in MS have been identified and a number of molecular parameters related to the ability to penetrate tissue have been calculated, including MS concentration, measured and calculated base ten logarithm of the octanol-water partition coefficient (Mlog P and Clog P), molecular volume (MgVol) and calculated molar refractivity (CMR).

Administration, Cutaneous↗
PubMed2003

QSAR of apoptosis induction in various cancer cells.

In continuing our QSAR study of apoptosis, we consider in this report the action of phenolic compounds on Ramos cells (non-Hodgkins B-cell lymphoma): the effect of O-8-thapsigargin analogues on human prostate cancer cells, Tsu-Pr-1 and the induction of apoptosis of a complex set of congeners on human fibrosarcoma cells HT 1080. The human prostate cancer cells activity is very similar to that of the Ramos cells. While the QSAR for the fibrosarcoma cells resembles that of our earlier study with L1210 leukemia cells. The two different types of QSAR suggest at least two quite different types of receptors for the induction of apoptosis.

Antineoplastic Agents↗
PubMed2003

Allosteric interactions and QSAR: on the role of ligand hydrophobicity.

A study of a very large database of QSAR (9100) has uncovered a few unusual examples where as one increases the hydrophobicity of the members of a set of congeners, activity decreases until at a certain point, activity begins to increase. Obviously a change in mechanism is involved. The only way we have found to rationalize this unusual event is by a change in the structure of the receptor. We have found this to occur with hemoglobin, a substance first used to define allosteric reactions.

Animals↗
PubMed2003

Searching for allosteric effects via QSAR. Part II.

Allosteric interactions have in the past been established by means of X-ray crystallography or careful study of a single molecule at a variety of concentrations. Here we report a method for using QSAR to establish a change in reaction mechanism by establishing an inversion point. That is, as polarizability of a member of a congeneric set of compounds is increased (as measured by CMR), activity at first decreases until, at the inversion, activity turns around and increases. Out of 23 examples, 14 have inversion points of 10+/-1. This includes a wide variety of receptors such as thrombin, 5-HT, dopamine, and tyrosine kinase acting with a variety of ligands.

Algorithms↗
PubMed2003

HIV-1 protease inhibitors: a comparative QSAR analysis.

An excellent example in the field of rational drug design is the discovery and development of more than a dozen drugs for the treatment of AIDS. The major targets for the development of new chemotherapeutic agents are Reverse Transcriptase and Protease, the enzymes encoded by HIV-1. The introduction of HIV-1 protease (HIV-1 PR) inhibitors, in particular, has drastically decreased the mortality and morbidity associated with AIDS. The inhibition of this enzyme results in production of immature and noninfectious virions. In the present review, a comparative quantitative structure activity relationship (QSAR) study of various peptidomimetic and non-peptidomimetic molecules investigated for their inhibitory activity has been reported. Among the various physicochemical properties studied, hydrophobicity, steric and electronic interactions are found to play important role in binding to the receptor.

Anti-HIV Agents↗
PubMed2002

The relative toxicity of substituted phenols reported in cigarette mainstream smoke.

Cigarette mainstream smoke (MS) contains a number of structurally diverse substituted phenols. Recent quantitative structure activity relationship (QSAR) studies on phenols show that substituted phenols with electron-releasing groups can form potentially toxic phenoxyl-free radicals. In contrast, substituted phenols with electron-withdrawing groups do not form phenoxyl-free radicals but exert their toxicity primarily through lipophilicity. The chemical structures of 253 different substituted phenols reported in MS have been described in sufficient detail to allow identification of the individual compounds. From a laterally validated equation based on published data on the toxic effects of phenols on cultured cells, the relative toxicity, on a molar basis, of the 253 MS phenols has been determined. Based on this scheme, the most toxic phenols in MS include, in descending order of toxicity, 2-(dimethylamino)-phenol, 2-ethyl-6-methyl-1,4-benzenediol, 2-methoxy-1,4-benzenediol, and 4-ethyl-2-methoxy-6-methylphenol. The least toxic phenols include, in ascending order of toxicity, 4-hydroxybenzoic acid and 3-hydroxybenzenepropanoic acid. In the human exposure situation, the toxicity of MS phenols is a complex interaction, with contributions made by the following factors: toxicity per mole; MS concentration; synergistic, additive or antagonistic interactions with other MS components; host susceptibility; metabolism; and individual smoking behavior and inhalation patterns. In the absence of data to the contrary, reduction in the number and concentration of toxic MS smoke components may be considered to be advantageous. Studies of this type can play an important role in identifying MS components for reduction or removal.

Animals↗