Synthesis and biological evaluation of carbamates derived from aminocombretastatin A-4 as vascular disrupting agents

• Published in: European journal of medicinal chemistry 2018-03, Vol.147, p.183-193
• Main Authors: Conesa-Milián, Laura, Falomir, Eva, Murga, Juan, Carda, Miguel, Meyen, Eef, Liekens, Sandra, Alberto Marco, J.
• Format: Article
• Language: English
• Subjects: Aminocombretastatin; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Carbamates; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Cell Cycle Checkpoints - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humans; Microtubules; Microtubules - drug effects; Microtubules - metabolism; Mitosis - drug effects; Molecular Structure; Polymerization - drug effects; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; Tubulin; Tubulin - metabolism; Vascular disrupting agents
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.01.058

A series of twenty-six carbamates derived from aminocombretastatin A-4 (AmCA-4) were synthesized and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest, microtubule network organization, apoptosis and endothelial tubular structures in vitro. The anti-proliferative activity of the synthetic carbamates was measured on several human tumor cell lines (i.e. HT-29, MCF-7, HeLa, A-549, MDA-MB-231, HL-60) as well as on the endothelial cell line HMEC-1 and the non-tumor cell line HEK-293. The compounds showed anti-proliferative activity in the nanomolar range thereby exceeding by far the activity of combretastatin A-4 (CA-4) and, in some cases, the activity of AmCA-4. The most active compounds proved to be the carbamates bearing chloro, bromo or methoxy groups in the meta position of the phenyl ring. Moreover, all carbamates inhibited in vitro tubulin polymerization, in a similar manner to that of CA-4 and AmCA-4 by interacting with the colchicine binding site in tubulin. The synthetic carbamates proved as active as AmCA-4 in causing mitotic arrest, as assessed in A549 human lung cancer cells, and disruption of the microtubule cellular network. Some selected carbamates induced apoptosis at concentrations as low as 10 nM, being more active than AmCA-4. Finally, these selected carbamates displayed a vascular disrupting activity on endothelial cells in a dose-dependent manner. In conclusion, our data indicate that carbamates derived from aminocombretastatin A-4 represent interesting lead compounds for the design of vascular disrupting agents. [Display omitted] •Several carbamates derived from combretastatin A-4 have been synthesized.•Most compounds completely inhibit in vitro tubulin polymerization.•Carbamates induced apoptosis in a dose-dependent manner.•Carbamates displayed a vascular disrupting activity of endothelial cells.•Some derivatives improves the effect showed by aminocombretastatin A-4