TY - JOUR
T1 - Design, synthesis and anticancer activity of novel valproic acid conjugates with improved histone deacetylase (HDAC) inhibitory activity
AU - Ibrahim, Tarek S.
AU - Sheha, Taghreed A.
AU - Abo-Dya, Nader E.
AU - AlAwadh, Mohammed A.
AU - Alhakamy, Nabil A.
AU - Abdel-Samii, Zakaria K.
AU - Panda, Siva S.
AU - Abuo-Rahma, Gamal El Din A.
AU - Mohamed, Mamdouh F.A.
N1 - Funding Information:
This project was funded by the Deanship of Scientific Research ( DSR ), King Abdulaziz University , Jeddah, under grant №. ( RG-9-166-38 ). The authors, therefore, gratefully acknowledge DSR technical and financial support.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/6
Y1 - 2020/6
N2 - Twenty-five valproic acid conjugates have been designed and synthesized. All target compounds were explored for their in vitro anti-proliferative activities using the MTT-based assay against four human cancer cell lines includingliver (HePG2), colon (HCT116), breast (MCF7) and cervical (HeLa) carcinoma cell lines. Out of six valproic acid-amino acid conjugates 2a-f. Only cysteine containing conjugate 2f showed the significant activity (IC50 9.10 µM against HePG2 and 6.81 µM against HCT116). However conjugate 2j showed broad-spectrum antitumor activity against all cell lines tested. In addition, conjugates 4j and 4k which contains phenyl hydrazide and hydroxamic acid group, respectively, also showed broad spectrum activity. Furthermore, six compounds were screened for HDAC 1-9 isozymes inhibitory activities. Compounds 2j, 4j and 4k manifested a higher inhibitory activity more than valproic acid but less than SAHA. In addition, the in vivo antitumor screening of 2j, 4j and 4k was done and the results have shown that 2j, 4j and 4k, particularly 4j, showed a significant decrease in tumor size and presented a considerable decrease in viable EAC count. Docking study of selectedcompound 4j revealed that it can bind nicely to the binding pocket of HDAC 1, 2, 3, 4 and HDAC 8. The results suggest that compounds 2j, 4j and 4k, particularly 4j, may be promising lead candidates for the development of novel targeted anti-tumor drug potentially via inhibiting HDACs.
AB - Twenty-five valproic acid conjugates have been designed and synthesized. All target compounds were explored for their in vitro anti-proliferative activities using the MTT-based assay against four human cancer cell lines includingliver (HePG2), colon (HCT116), breast (MCF7) and cervical (HeLa) carcinoma cell lines. Out of six valproic acid-amino acid conjugates 2a-f. Only cysteine containing conjugate 2f showed the significant activity (IC50 9.10 µM against HePG2 and 6.81 µM against HCT116). However conjugate 2j showed broad-spectrum antitumor activity against all cell lines tested. In addition, conjugates 4j and 4k which contains phenyl hydrazide and hydroxamic acid group, respectively, also showed broad spectrum activity. Furthermore, six compounds were screened for HDAC 1-9 isozymes inhibitory activities. Compounds 2j, 4j and 4k manifested a higher inhibitory activity more than valproic acid but less than SAHA. In addition, the in vivo antitumor screening of 2j, 4j and 4k was done and the results have shown that 2j, 4j and 4k, particularly 4j, showed a significant decrease in tumor size and presented a considerable decrease in viable EAC count. Docking study of selectedcompound 4j revealed that it can bind nicely to the binding pocket of HDAC 1, 2, 3, 4 and HDAC 8. The results suggest that compounds 2j, 4j and 4k, particularly 4j, may be promising lead candidates for the development of novel targeted anti-tumor drug potentially via inhibiting HDACs.
KW - Anticancer
KW - HDAC inhibitors
KW - Histone deacetylases
KW - Molecular Docking
KW - Valproic acid
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U2 - 10.1016/j.bioorg.2020.103797
DO - 10.1016/j.bioorg.2020.103797
M3 - Article
C2 - 32247939
AN - SCOPUS:85082706397
SN - 0045-2068
VL - 99
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 103797
ER -