Quantitative structure activity relationship (QSAR) studies of some substituted benzenesulphonyl glutamines as tumour suppressors.

As a part of a composite programme of rational drug design (RDD), we had synthesized some substituted benzenesulphonyl glutamines and evaluated their inhibitory activities against Ehrlich Ascites Carcinoma (EAC) cell line in Swiss albino mice. Quantitative structure activity relationship (QSAR) studies of these inhibitory activities using Fujita-Ban model as well as Modified Hansch-Fujita model gave excellent correlations (correlation coefficient r = 0.89 and 0.82 respectively). These results could be useful in designing 'lead' compound with potent inhibitory activity on DNA and RNA synthesis and tumour development.

Ethinyl estradiol: its interaction on blood-lipid.

Lipophilicity (log P) of the drug plays an important role when drug reaches in the critical reaction site, i.e., active site cum receptors where the major constituent is lipid moieties. The drug molecule may be responsible for altering the lipid constituents, which is measured in terms of phosphorus content and can be explained by their fatty acid changes that are linked with biological effect of the drug. Having considered the lipophilicity of ethinyl estradiol (log P = 3.67), its interactions with the whole lipid of goat blood have been investigated along with fatty acid changes and lipid peroxidation phenomena. There was significant loss of phosphorus content of phospholipid and change of fatty acid constituents of whole lipid. This may be ascribed to binding affinity of ethinyl estradiol with lipid constituents in blood. Lipid binding potential of the drug may have role in its therapeutic effect. The peroxidation induced by drug has been quantitatively measured along with its suppression by using antioxidant. The results reveal that ethinyl estradiol caused significant extent of lipid peroxidation. Ascorbic acid, a promising antioxidant could significantly reduce drug induced lipid peroxidation.

Effect of aspirin on blood-lipid interaction and lipid peroxidation phenomena in relation to partition coefficient and biological activity.

Considering the lipophilicity of aspirin (log P = -1.15), a significant contributor to its action mechanism, interaction of the drug with the whole lipids of goat blood have been investigated using phospholipid binding and lipid peroxidation phenomena as the parameters under investigation. The lipid content change along with the peroxidation induced by aspirin and its suppression with ascorbic acid had been quantitatively measured. Significant loss in phospholipid was observed after incubation of whole blood with aspirin in varying periods of time. This may be ascribed to binding affinity of aspirin with lipid constituents in blood, which may have potential role in its therapeutic effect. Lipid peroxidation induction potential of aspirin caused significant extent of peroxidation. Ascorbic acid, an antioxidant could significantly reduce aspirin induced lipid peroxidation.

Evaluation of glutathione and ascorbic acid as suppressors of drug-induced lipid peroxidation.

In different sets of experiment lipid peroxidation induction capacity of two drugs, viz., ceftizoxime sodium, a third generation cephalosporin antibiotic, and acyclovir, an antiviral agent, was studied using goat whole blood as the lipid source. Ceftizoxime sodium caused significant extent of lipid peroxidation. Lipid peroxidation being a toxicity mediating process, such observation may be related to the toxic potential of the drug. Insignificant induction of lipid peroxidation was found in case of acyclovir and this is in good agreement with the safety record of the drug. Glutathione and ascorbic acid could significantly reduce ceftizoxime sodium induced lipid peroxidation, suggesting that free radical scavenging action of antioxidants may be exploited by possible antioxidant co-therapy to reduce iatrogenicity of the drug in persons with impaired endogenous antioxidant defence. Glutathione and ascorbic acid appear to be promising candidates for further investigation in this regard.

Effect of two cardiac glycosides, digitoxin and digoxin on blood lipids.

Two cardiac glycosides, namely digitoxin and digoxin when treated with goat blood, were found to alter the lipid constitution as measured by their phosphorus content, fatty acid composition and malonaldehyde content. There was significant increase in the poly-unsaturated fatty acids (PUFA) and malonaldehyde contents in blood treated with these drugs. Possible correlation between the lipophilicity of the drugs and their biological activity is discussed.

Effect of propranolol hydrochloride on blood cell lipids in relation to partition coefficient and biological activity.

Considering the high lipophilicity of propranolol (log P = 3.56), its interactions with the cell membrane lipids of goat blood have been investigated. It is observed that lipid loss after incubation of blood cells with propranolol hydrochloride in salt glucose medium for varying periods of time was accompanied with significant increases in PUFAs. Amongst the PUFAs studied the omega 3 and omega 6 fatty acids, the two important precursors of eicosenoids, have shown increase in varying amounts. This phenomenon is presumably responsible for the significant cardiovascular activity of this drug.

Correlation of phospholipid loss in goat whole blood with solvochromic properties of antiamebics like emetine, metronidazole and diloxanide furoate.

Phospholipid content of whole blood lipid decreases significantly when goat blood is incubated for different length of time with different amebicidal agents (e.g., emetine, metronidazole and diloxanide furoate). The plots of relative per cent phosphate loss against incubation period show biphasic nature and suggest that the rates of phospholipid loss bears some relation with the drug's lipophilicity (log P in 1 octanol/water system). The absolute phospholipid loss seems to be governed by the drug's aquasolubility. Implication of these finding were discussed in terms of their clinical profiles assuming that the loss of phospholipid is due to drug's binding with the phospholipid layer in amebic cyst-coat, being the first step which may trigger a chain of events leading to the onset of drug action.

Effect of lignocaine on blood lipid in relation to partition coefficient and biological activity.

To correlate lipophilicity of lignocaine with changes in lipid composition of blood as a result of in vitro incubation with the drug, phosphorus content and fatty acid compositions of blood lipids before and after lignocaine treatment have been compared with those of a standard phospholipid, lecithin, under similar conditions of drug treatment. The change in fatty acid constituents has been correlated with the biological activity (both therapeutic and toxic) of lignocaine.