Synthesis and Cytotoxic Activity of a New Group of Heterocyclic Analogues of the Combretastatins

Molecules

Alla V. Lipeeva¹  Elvira E. Shults¹  Makhmut M. Shakirov¹  Mikhail A. Pokrovsky² 

[1] Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, Novosibirsk 630090, Russia; E-Mails:;Medicinal Department, Novosibirsk State University, Pirogova St. 2, Novosibirsk 630090, Russia; E-Mails:

关键词: furocoumarins;    oreoselone;    psoralen;    Sonogashira coupling;    semi-hydrogenation;    combretastatins;    cytotoxicity;   

DOI  :  10.3390/molecules19067881

来源: mdpi

【 摘 要 】

A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6–8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9–11. The methoxy-, hydroxyl- and formyl- substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD₅₀ values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.