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

Abstract

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 CTD 50 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.

Plant coumarins: XV. Oreoselone in the synthesis of 3-[(Z)-alkenyl]- and 3-(1H-1,2,3-triazol-4-yl)psoralens

“…3-(Trimethylsilylethynyl)furocoumarin (14) [18], 2,4-dimethoxyphenylacetylene (3c) [33], 2,4-dihydroxyphenylacetylene (3d) [33], methyl 2-acetylamino-5-ethynylbenzoate (3e) [34], 4-(2-azidoethyl)phenol (15) [30], 4-(bromomethyl)-2,3,5,6-tetramethylphenol (25) [35,36], 4-(bromomethyl)-2,6-ditert-butylphenol (26) [37,38], 4-(2-bromoethyl)-2,6di-tert-butylphenol (27) [39], 4-(3-chloropropyl)-2,6-(di-tert-butyl)phenol (28) [40], and dichlorobis(tri-phenylphosphine)palladium(II) [41] were synthesized by known methods.…”

“…We have recently proposed a procedure for the synthesis of furocoumarins with an aromatic, heterocyclic, (E)-(2-phenylethenyl), or phenylalkynyl substituent on C 3 by palladium-catalyzed cross-coupling of 2-isopropyl-3-(trifluoromethanesulfonyloxy)psoralen (2) [15][16][17][18]. (Z)-3-(2-Phenylethenyl)furocoumarins were prepared following the approach [18] including crosscoupling of trifluoromethanesulfonate 2 with terminal alkynes 3a-3e and subsequent partial hydrogenation of the C≡C triple bond (Scheme 1).…”

Microtubule targeting agents in glioma

“…During the last three years, aided by the increasing availability and sophistication of in silico modeling algorithms and of high-throughput cell based screening assays, intense efforts to discover new antimitotic therapeutic agents have led to the discovery of a vast array of novel analogs of colchicine and combretastatin-A, some displaying both anti-mitotic as well as anti-vascular activity like: MDS-11P (39), indole compounds II and IAT (40), cis-constrained analogs of combretastatin A4: compounds 11 and 19 (41), cis 3-b (42), DAT-230 (43), ketone 24-b (44), phenothiazine derivative 21 (45), 1,1-diaryl-2-methoxyethylenes 4b and 4e (46), combretazet-3 (CAZ-3) (47), benzoimidazole analog 5 (48), compound 3-HCl (AG119) (49), furocoumarin analogs of combretastatins: compounds 2 and 3 (50), and the IsoCombretaQuinazolines (isoCoQ) compounds 4b, 4c and 4d (51).…”

Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

“…CA-4 and its water-soluble prodrugs such as CA-4P (fosbretabulin and zybrestat) [4] and AVE8062 (ombrabulin) [5] have entered clinical trials for the treatment of anaplastic thyroid cancer and other solid tumors in both USA and Europe [6]. Due to its small molecular weight and simple structure, an impressive number of synthetic research was carried out over the past decades [7][8][9][10].…”