José M. Padrón

Sphingolipids in anticancer therapy.

Sphingolipids constitute a broad class of compounds with many biological functions. The sphingolipid metabolites ceramide and sphingosine are potent apoptosis inducers and produce cell cycle arrest, whereas sphingosine-1-phosphate promotes cellular growth and differentiation. Herein, the effects of sphingolipids and their analogs on diverse signaling pathways implicated in the apoptotic process are highlighted. The relatively simple chemical structure of these compounds has led to several strategies for their total synthesis. Those methods have contributed to the development and biological study of several analogs that present diverse degree of modification from the original structure. This article catalogues many of the recently developed synthetic analogs that act on diverse aspects of sphingolipid metabolism. A description of known enzyme inhibitors of the sphigolipids pathway is also given. Finally, diverse new sphingolipid-like antitumor agents isolated from marine sources are presented. This contribution opens the way for future development of new sphingolipid analogs that might be useful in cancer chemotherapy.

Belizeanolide, a Cytotoxic Macrolide from the Dinoflagellate Prorocentrum belizeanum†

Marine dinoflagellates produce many of the most active and complex secondary metabolites found in nature. In fact, some of these molecules have had an extraordinary impact upon different areas of life science such as human health, seafood control analysis, pharmacology, natural product chemistry, and the economics of the fishery industry, thus promoting new developments in all these areas. In particular, the dinoflagellates of the genus Prorocentrum, recognized as co-responsible of the diarrhetic shellfish poisoning (DSP) syndrome, are known to produce several unique bioactive secondary metabolites with a broad diversity of skeletons, including “linear” polycyclic compounds and macrolides. Herein, we report on the isolation, structure determination, partial relative stereochemistry assignment, and biological activity of the first member of a new class of macrolides, belizeanolide (1), which is produced by the marine dinoflagellate Prorocentrum belizeanum, together with its open form belizeanolic acid (2). Belizeanolide and belizeanolic acid were isolated as optically active white amorphous solids ([a] D = 9.2 degcm g 1 dm 1 (c = 0.0013 gcm , in methanol) and [a] D = 5.2 degcm g 1 dm 1 (c = 0.0016 gcm , in methanol), respectively) from the culture media of the dinoflagellate. The clarified culture media was slowly passed through a polyaromatic adsorbent resin that was successively extracted with methanol. By using this procedure, 1.52 g of crude extract was obtained from 750 L of culture. Next the extract was successively purified by several chromatographic steps to

Synthesis and antiproliferative activity of 2,4-disubstituted 6-aryl-7H-pyrrolo[3,2-d]pyrimidin-7-one 5-oxides.

A series of 2,4-disubstituted 6-aryl-7H-pyrrolo[3,2-d]pyrimidin-7-one 5-oxides were synthesized and in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, HBL-100, HeLa, SW1573, T-47D, and WiDr. The most potent analog induced considerably growth inhibition in the range 0.35-2.0microM. Cell cycle studies in the breast and lung cancer cells revealed arrest in the G(2)/M compartment. The results showed that the title compounds bearing alkylamino or dialkylamino moieties in position 2 of the pyrimidine ring are more active than those bearing hydrogen or methylthio groups.

Tessaric acid derivatives induce G2/M cell cycle arrest in human solid tumor cell lines

A series of analogs were synthesized in a straightforward manner from naturally available sesquiterpenes ilicic acid and tessaric acid. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, HBL-100, HeLa, SW1573, T-47D and WiDr. The most potent analog induced considerably growth inhibition in the range 1.9-4.5 microM. Cell cycle studies for tessaric acid derivatives indicated a prominent arrest of the cell cycle at the G(2)/M phase. Damage to the cells was permanent as determine by the so called 24+24 drug schedule.

γ-Lactones α,β- and β,γ-fused to carbocycles as novel antiproliferative drugs

A set of gamma-lactones alpha,beta-fused and beta,gamma-fused to carbocycles have been synthesized and evaluated for their in vitro antiproliferative activities using the human cancer cell lines SW1573 (lung), T-47D (breast) and WiDr (colon). The compounds are obtained by intramolecular ring closing metathesis of the corresponding dienes. Active compounds exhibited GI(50) values in the range 8-18 microM. A structure-activity relationship is also discussed.