Abstract
The cantharidinimide derivatives, 5a–h, including sulfanilamides containing pyrimidyl, pyrazinyl, hydrogen, thiazolyl, and oxazolyl groups were synthesized. Modification of cantharidinimide by means of the reaction of activated aziridine ring opening led to the discovery of a novel class of antitumor compounds. The analogues 10i–k, 11l–n, 12o–p, and 16q–s were obtained from treating cantharidinimide 6 and analogues (7, 8, and 13) with activated aziridines, which produced a series of ring-opened products including normal and abnormal types. Some of these compounds showed cytotoxic effects in vitro against HL-60, Hep3B, MCF7, and MDA-MB-231 cancer cells. The most potent cytostatic compound, N-cantharidinimido-sulfamethazine (5a), exhibited anti-HL-60 and anti-Hep3B cell activities. Two compounds 5g and 5h displayed slight effects on the Hep3B cell line, while the other compounds produced no response in these four cell lines.
Highlights
Cantharidin 1 (Figure 1), isolated from Mylabris caraganae and various other insects, is a terpenoid and has a high vesicant potency [1]
On the aromatic ring (X) exhibited increased cytotoxicity to cancer cell lines. We used this feature and synthesized different imines to study their cytotoxic effects [31]. These results showed that cantharidinimine derivatives had greater cytotoxic effects than cantharidinimides
Some researchers screened their synthetic compounds against human cancer cell lines and used a COMPARE analysis to evaluate the anticancer activity and predict the probable mechanism [27,39,40,41,42]
Summary
Cantharidin 1 (Figure 1), isolated from Mylabris caraganae and various other insects, is a terpenoid and has a high vesicant potency [1]. A number of modified cantharidin analogues were synthesized and their anticancer activities against a wide range of human tumor cell lines were evaluated [21,22,23,24,25,26,27]. Cantharidinimine derivative 2 (Figure 1), which has a sulfanyl group, exhibited a 50% inhibitory concentration (IC50 ) value of 6 μM against HL-60 cells as did cantharidin (IC50 value of 7.2 μM). Cantharidinimides and their analogues display inhibition of the inducible nitric oxide (NO) synthase (iNOS) pathway, and they inhibited NO synthase activity by more than 90%. In order to find new cantharidinimides and related imides containing the sulfonamide group, we synthesized sulfonamido-ethyldicarboximide derivatives (10i–k, 11l–n, 12o–p, and 16q–s) and tested their cytotoxic activities
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