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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

General structure of designed pyrazole derivatives
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Figure 3: General structure of designed pyrazole derivatives

Mentions: Virtual pyrazole derivatives (Figure 3(Fig. 3)) showing significant interactions in molecular docking, this provided guidance for selection of derivatives to be synthesized for better antiproliferative activity. Literature survey reveals that, VEGFR-2 kinase inhibitors known to interact with amino acids such as Asp 1046, Glu 885, Cys 1045, Val 895, Arg 1027, Phe 1047, Ile 1025, etc., at the active site. While Asp 1046, Glu 885, and Arg 1027 tend to form hydrogen bonds with the ligand, Phe 1047 and Val 899 undergo stacking interactions with aromatic ring of ligand (Meenakshi et al., 2013[23]; Sanphanya et al., 2013[29]; Borzilleri et al., 2005[4]; Dai et al., 2008[9]). In the present study, the designed structures were docked into VEGFR-2 kinase active site to explore to know that experimental compounds have similar interactions as that of known VEGFR-2 inhibitors. Docking of compound 4f showed two hydrogen bond interactions (NH of ring D and Ile 1044; d=1.88 Ao, OCH3 of ring B and Lys 868; d=3.06 Ao) and ring C showed stacking interaction with Arg 1027 (d=3.64 Ao). Moreover, ring B was surrounded by Asp 1046 and Glu 885 and this may be the reason for superior activity of compound 4f among the series 4a-4g in antiproliferative studies. Compound 4e, though it does not show any hydrogen bond interactions in docking, but elicited moderate antiproliferative activity studies, which might be due to its close association with active site amino acids such as Asp 1046, Lys 868, His 1026 and Glu 885. Compound 5c exhibited three hydrogen bond interactions (oxygen of OH and Arg 1027; d=2.28 Ao, hydrogen of OH and Ile 1025; d=1.23 Ao, C=O and Ile 1025; d=2.89 Ao) and ring D stacking interaction with Arg 1027. Apart from this, compound was surrounded by Asp 1046, Glu 885 and Lys 868. The introduction of -CH2COOH in the series 5a-5g provided additional hydrogen bond interactions with the active site amino acids of VEGFR-2 and this might have contributed for better activity of these series as compared to other series of compounds 4a-4g, which is supported by results obtained in antiangiogenesis, in vitro and in vivo antiproliferative activity. Data pertaining to the interaction of pyrazolyl tetrazoles 4a-4g and pyrazolyl tetrazole acetic acids 5a-5g with active site amino acids of VEGFR-2 was given in Table 3(Tab. 3). The two-dimensional and three-dimensional representations of compound 5c and 4f were given under Figures 2(Fig. 2) and 4(Fig. 4).


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)

General structure of designed pyrazole derivatives
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: General structure of designed pyrazole derivatives
Mentions: Virtual pyrazole derivatives (Figure 3(Fig. 3)) showing significant interactions in molecular docking, this provided guidance for selection of derivatives to be synthesized for better antiproliferative activity. Literature survey reveals that, VEGFR-2 kinase inhibitors known to interact with amino acids such as Asp 1046, Glu 885, Cys 1045, Val 895, Arg 1027, Phe 1047, Ile 1025, etc., at the active site. While Asp 1046, Glu 885, and Arg 1027 tend to form hydrogen bonds with the ligand, Phe 1047 and Val 899 undergo stacking interactions with aromatic ring of ligand (Meenakshi et al., 2013[23]; Sanphanya et al., 2013[29]; Borzilleri et al., 2005[4]; Dai et al., 2008[9]). In the present study, the designed structures were docked into VEGFR-2 kinase active site to explore to know that experimental compounds have similar interactions as that of known VEGFR-2 inhibitors. Docking of compound 4f showed two hydrogen bond interactions (NH of ring D and Ile 1044; d=1.88 Ao, OCH3 of ring B and Lys 868; d=3.06 Ao) and ring C showed stacking interaction with Arg 1027 (d=3.64 Ao). Moreover, ring B was surrounded by Asp 1046 and Glu 885 and this may be the reason for superior activity of compound 4f among the series 4a-4g in antiproliferative studies. Compound 4e, though it does not show any hydrogen bond interactions in docking, but elicited moderate antiproliferative activity studies, which might be due to its close association with active site amino acids such as Asp 1046, Lys 868, His 1026 and Glu 885. Compound 5c exhibited three hydrogen bond interactions (oxygen of OH and Arg 1027; d=2.28 Ao, hydrogen of OH and Ile 1025; d=1.23 Ao, C=O and Ile 1025; d=2.89 Ao) and ring D stacking interaction with Arg 1027. Apart from this, compound was surrounded by Asp 1046, Glu 885 and Lys 868. The introduction of -CH2COOH in the series 5a-5g provided additional hydrogen bond interactions with the active site amino acids of VEGFR-2 and this might have contributed for better activity of these series as compared to other series of compounds 4a-4g, which is supported by results obtained in antiangiogenesis, in vitro and in vivo antiproliferative activity. Data pertaining to the interaction of pyrazolyl tetrazoles 4a-4g and pyrazolyl tetrazole acetic acids 5a-5g with active site amino acids of VEGFR-2 was given in Table 3(Tab. 3). The two-dimensional and three-dimensional representations of compound 5c and 4f were given under Figures 2(Fig. 2) and 4(Fig. 4).

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