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Design, synthesis, in silico toxicity prediction, molecular docking, and evaluation of novel pyrazole derivatives as potential antiproliferative agents.

Ravula P, Vamaraju HB, Paturi M, Chandra Jn NS, Kolli S - EXCLI J (2016)

Bottom Line: Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively.In silico prediction of toxicities, and drug score profiles of designed compounds are promising.A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Guru Nanak Institutions Technical Campus, School of Pharmacy, Jawaharlal Nehru Technological University, Hyderabad- 501301, India.

ABSTRACT
A new series of pyrazole derivatives were designed by docking into vascular endothelial growth factor receptor-2 (VEGFR-2) kinase active site. The designed compounds were synthesized and evaluated for in vitro antiproliferative activity against HT-29 colon and PC-3 prostate cancer cell lines, and angioinhibitory activity in chorioallantoic membrane (CAM) model. Based on the obtained antiproliferative activity results of in vitro and CAM assay, compounds 4b, 4c, 4f, 5b, 5c and 5f were selected, and tested for anticancer activity using in vivo ehrlich ascites carcinoma (EAC) bearing mice. Compound 5c showed the highest in vitro antiproliferative activity against HT-29 and PC-3 with IC50 values of 6.43 µM and 9.83 µM respectively and comparable to reference drug Doxorubicin. Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively. Moreover, compound 5c demonstrated significant reduction of microvessel density (MVD) in CAM assay. In silico prediction of toxicities, and drug score profiles of designed compounds are promising. A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity.

No MeSH data available.


Related in: MedlinePlus

Predicted toxicity parameters of synthesized 4a-4g and 5a-5g compounds
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T4: Predicted toxicity parameters of synthesized 4a-4g and 5a-5g compounds

Mentions: Site of metabolism prediction process focuses on pinpointing the site or moiety in a chemical structure, which is most likely to undergo metabolization, hence aiding with decision support in the drug optimization process. A positive result implies susceptibility of the moiety for metabolism. Negative results indicate the resistance of the moiety for undergoing metabolism. Cytochrome P450 (CYP) isoforms are responsible for metabolism of many drugs. Inhibition of this CYP isoforms results in decreased elimination and change in metabolic pathways of their substrates, which is the major cause of adverse drug-drug interactions. It is, therefore, essential to trace out the compounds potential for CYP inhibition at an early stage of drug discovery. The ability of the designed compounds to inhibit five major drug metabolizing CYP isoforms (i.e. CYP3A4, CYP2D6, CYP2C19, CYP2C9 and CYP1A2) was predicted by using a unified proteochemometric (PCM) model in bioclipse software. A positive result implies that compound computationally predicted to inhibit CYP isoforms and the negative sign indicates that the compound computationally predicted to have no ability to inhibit CYP isoforms. The designed pyrazolyl tetrazoles 4a-4g and 5a-5g have shown differential effect on the inhibition of CYP isoforms. While compounds 4a-4c predicted to show positive on the inhibition of CYP isoforms and the remaining compounds exhibited negative effect. It can be assumed that the presence of -CH2COOH moiety in 5a-5g series may be responsible for the negative effect on inhibition of CYP isoforms. The results displayed in Table 4(Tab. 4), showed that all the compounds are likely to exhibit low probable toxicity risks as revealed by computational in silico studies.


Design, synthesis, in silico toxicity prediction, molecular docking, and evaluation of novel pyrazole derivatives as potential antiproliferative agents.

Ravula P, Vamaraju HB, Paturi M, Chandra Jn NS, Kolli S - EXCLI J (2016)

Predicted toxicity parameters of synthesized 4a-4g and 5a-5g compounds
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834670&req=5

T4: Predicted toxicity parameters of synthesized 4a-4g and 5a-5g compounds
Mentions: Site of metabolism prediction process focuses on pinpointing the site or moiety in a chemical structure, which is most likely to undergo metabolization, hence aiding with decision support in the drug optimization process. A positive result implies susceptibility of the moiety for metabolism. Negative results indicate the resistance of the moiety for undergoing metabolism. Cytochrome P450 (CYP) isoforms are responsible for metabolism of many drugs. Inhibition of this CYP isoforms results in decreased elimination and change in metabolic pathways of their substrates, which is the major cause of adverse drug-drug interactions. It is, therefore, essential to trace out the compounds potential for CYP inhibition at an early stage of drug discovery. The ability of the designed compounds to inhibit five major drug metabolizing CYP isoforms (i.e. CYP3A4, CYP2D6, CYP2C19, CYP2C9 and CYP1A2) was predicted by using a unified proteochemometric (PCM) model in bioclipse software. A positive result implies that compound computationally predicted to inhibit CYP isoforms and the negative sign indicates that the compound computationally predicted to have no ability to inhibit CYP isoforms. The designed pyrazolyl tetrazoles 4a-4g and 5a-5g have shown differential effect on the inhibition of CYP isoforms. While compounds 4a-4c predicted to show positive on the inhibition of CYP isoforms and the remaining compounds exhibited negative effect. It can be assumed that the presence of -CH2COOH moiety in 5a-5g series may be responsible for the negative effect on inhibition of CYP isoforms. The results displayed in Table 4(Tab. 4), showed that all the compounds are likely to exhibit low probable toxicity risks as revealed by computational in silico studies.

Bottom Line: Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively.In silico prediction of toxicities, and drug score profiles of designed compounds are promising.A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Guru Nanak Institutions Technical Campus, School of Pharmacy, Jawaharlal Nehru Technological University, Hyderabad- 501301, India.

ABSTRACT
A new series of pyrazole derivatives were designed by docking into vascular endothelial growth factor receptor-2 (VEGFR-2) kinase active site. The designed compounds were synthesized and evaluated for in vitro antiproliferative activity against HT-29 colon and PC-3 prostate cancer cell lines, and angioinhibitory activity in chorioallantoic membrane (CAM) model. Based on the obtained antiproliferative activity results of in vitro and CAM assay, compounds 4b, 4c, 4f, 5b, 5c and 5f were selected, and tested for anticancer activity using in vivo ehrlich ascites carcinoma (EAC) bearing mice. Compound 5c showed the highest in vitro antiproliferative activity against HT-29 and PC-3 with IC50 values of 6.43 µM and 9.83 µM respectively and comparable to reference drug Doxorubicin. Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively. Moreover, compound 5c demonstrated significant reduction of microvessel density (MVD) in CAM assay. In silico prediction of toxicities, and drug score profiles of designed compounds are promising. A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity.

No MeSH data available.


Related in: MedlinePlus