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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

(A) Two-dimensional representation of the interacting mode of 5c with VEGFR-2 kinase. (B) Three-dimensional structural model of compound 5c (purple) into VEGFR-2 kinase
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Figure 2: (A) Two-dimensional representation of the interacting mode of 5c with VEGFR-2 kinase. (B) Three-dimensional structural model of compound 5c (purple) into VEGFR-2 kinase

Mentions: The antiangiogenic activity was screened by observing microvessel density (MVD) count, which is important tool to assess the neovasculature in tumors. Vehicle control group was treated with 0.1 % DMSO did not show any change in vasculature. CAM assay results showed reduced MVD count for the synthesized pyrazole derivatives. There is remarkable correlation observed between the docking studies and angioinhibitory activity. Among the tested compounds, compound 5c exhibited the lowest MVD count showed significant docking interactions with the VEGFR-2 active site (Figure 2(Fig. 2)).


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)

(A) Two-dimensional representation of the interacting mode of 5c with VEGFR-2 kinase. (B) Three-dimensional structural model of compound 5c (purple) into VEGFR-2 kinase
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: (A) Two-dimensional representation of the interacting mode of 5c with VEGFR-2 kinase. (B) Three-dimensional structural model of compound 5c (purple) into VEGFR-2 kinase
Mentions: The antiangiogenic activity was screened by observing microvessel density (MVD) count, which is important tool to assess the neovasculature in tumors. Vehicle control group was treated with 0.1 % DMSO did not show any change in vasculature. CAM assay results showed reduced MVD count for the synthesized pyrazole derivatives. There is remarkable correlation observed between the docking studies and angioinhibitory activity. Among the tested compounds, compound 5c exhibited the lowest MVD count showed significant docking interactions with the VEGFR-2 active site (Figure 2(Fig. 2)).

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