Total Syntheses and Preliminary Biological Evaluation of Brominated Fascaplysin and Reticulatine Alkaloids and Their Analogues

Abstract

A simple approach toward the synthesis of the marine sponge derived pigment fascaplysin was used to obtain the marine alkaloids 3-bromofascaplysin and 3,10-dibromofascaplysin. These compounds were used for first syntheses of the alkaloids 14-bromoreticulatate and 14-bromoreticulatine. Preliminary bioassays showed that 14-bromoreticulatine has a selective antibiotic (to Pseudomonas aeruginosa) activity and reveals cytotoxicity toward human melanoma, colon, and prostate cancer cells. 3,10-Dibromofascaplysin was able to target metabolic activity of the prostate cancer cells, without disrupting cell membrane’s integrity and had a wide therapeutic window amongst the fascaplysin alkaloids.

Efficacy and Mechanism of Action of Marine Alkaloid 3,10-Dibromofascaplysin in Drug-Resistant Prostate Cancer Cells

“…Overcoming drug resistance is a major challenge in the treatment of advanced prostate cancer. 3,10-Dibromofascaplysin (DBF, Figure 1A)-a new halogenated fascaplysin-showed promising activity in previous screening experiments [20]. Therefore, we evaluated cytotoxicity of this marine alkaloid in different human drug-resistant prostate cancer cell lines in vitro.…”

“…Recently, we identified DBF to be active in human prostate cancer cells during a small-scale screening of semi-synthetic fascaplysin derivatives. In contrast to the other synthesized derivatives, DBF revealed a smooth cytotoxicity profile, suggesting a wide therapeutic window [20]. In addition, DBF was found to affect cellular metabolism, which further leads to cancer cell death [20].…”

“…In contrast to the other synthesized derivatives, DBF revealed a smooth cytotoxicity profile, suggesting a wide therapeutic window [20]. In addition, DBF was found to affect cellular metabolism, which further leads to cancer cell death [20]. In the current research we evaluated the activity of DBF in human prostate cancer cell lines harboring different levels of drug resistance to currently available standard therapies.…”

“…This alkaloid possesses a 12H-pyrido[1,2-a:3,4-b']diindole core [11] and reveals a broad spectrum of biological activities, including antifungal, antibacterial, antiviral, antimalarial, and antitumor effects [11][12][13]. Its antitumor activity was evaluated in different human cancer cells lines including lung, prostate, breast, and colorectal cancer, melanoma and leukemia [13][14][15][16][17][18][19][20]. Fascaplysin and similar alkaloids seem to mediate their activity by inhibition of cyclin-dependent kinase 4 (CDK4) and intercalation with dsDNA, which leads to a G1-phase cell cycle arrest and ultimately to the apoptotic cancer cell death [11,12,21,22].…”

“…3,10-Dibromofascaplysin (DBF) is a novel halogenated fascaplysin alkaloid initially isolated from the marine sponge Fascaplysinopsis reticulata [28] and later synthesized by our group [20]. Recently, we identified DBF to be active in human prostate cancer cells during a small-scale screening of semi-synthetic fascaplysin derivatives.…”