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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

The total synthetic pathway. Reagents and conditions: (a) NH2OH.HCl, NaOH, EtOH, reflux, 2h; (b) acetic anhydride, reflux, 1h; (c) NaN3, DMF, triethyl ammonium chloride, reflux, 24-48 h; (d) ethyl chloroacetate, K2CO3, dry acetone, reflux, 4 h; and (e) NaOH, EtOH, reflux, 4h
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Figure 1: The total synthetic pathway. Reagents and conditions: (a) NH2OH.HCl, NaOH, EtOH, reflux, 2h; (b) acetic anhydride, reflux, 1h; (c) NaN3, DMF, triethyl ammonium chloride, reflux, 24-48 h; (d) ethyl chloroacetate, K2CO3, dry acetone, reflux, 4 h; and (e) NaOH, EtOH, reflux, 4h

Mentions: Based on the above consideration, we designed a new series of pyrazole derivatives using molecular docking studies with the help of software MOE 2008 into the active site of VEGFR-2 kinase. Virtual screening was focused on experimental molecules showing significant interactions as that of marketed drugs used in clinical practice, to the specific active site amino acids of the receptor. Promising molecules in this docking study were synthesized as given in the Figure 1(Fig. 1). The synthesized compounds were screened for in vitro antiproliferative activity against two cell lines namely HT-29 colon and PC-3 prostate and in vivo using chorioallantoic membrane (CAM) model. Based on the obtained results of these assays, compounds 4b, 4c, 4f, 5b, 5c and 5f were tested for in vivo anticancer using ehrlich ascites carcinoma (EAC) bearing mice.


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)

The total synthetic pathway. Reagents and conditions: (a) NH2OH.HCl, NaOH, EtOH, reflux, 2h; (b) acetic anhydride, reflux, 1h; (c) NaN3, DMF, triethyl ammonium chloride, reflux, 24-48 h; (d) ethyl chloroacetate, K2CO3, dry acetone, reflux, 4 h; and (e) NaOH, EtOH, reflux, 4h
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The total synthetic pathway. Reagents and conditions: (a) NH2OH.HCl, NaOH, EtOH, reflux, 2h; (b) acetic anhydride, reflux, 1h; (c) NaN3, DMF, triethyl ammonium chloride, reflux, 24-48 h; (d) ethyl chloroacetate, K2CO3, dry acetone, reflux, 4 h; and (e) NaOH, EtOH, reflux, 4h
Mentions: Based on the above consideration, we designed a new series of pyrazole derivatives using molecular docking studies with the help of software MOE 2008 into the active site of VEGFR-2 kinase. Virtual screening was focused on experimental molecules showing significant interactions as that of marketed drugs used in clinical practice, to the specific active site amino acids of the receptor. Promising molecules in this docking study were synthesized as given in the Figure 1(Fig. 1). The synthesized compounds were screened for in vitro antiproliferative activity against two cell lines namely HT-29 colon and PC-3 prostate and in vivo using chorioallantoic membrane (CAM) model. Based on the obtained results of these assays, compounds 4b, 4c, 4f, 5b, 5c and 5f were tested for in vivo anticancer using ehrlich ascites carcinoma (EAC) bearing mice.

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