Amakusamine from a Psammocinia sp. Sponge: Isolation, Synthesis, and SAR Study on the Inhibition of RANKL-Induced Formation of Multinuclear Osteoclasts

Abstract

A simple methylenedioxy dibromoindole alkaloid, amakusamine (1), was isolated from a marine sponge of the genus Psammocinia, and its structure was determined from spectroscopic data, time-dependent density-functional theory calculations, and synthesis. Compound 1 inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts with an IC 50 value of 10.5 μM in RAW264 cells. The structure−activity relationship of 1 was also investigated with synthetic derivatives.

Indole-Containing Natural Products 2019–2022: Isolations, Reappraisals, Syntheses, and Biological Activities

“…Compounds 231 and 232 were isolated from the bark of Voacanga africana , and they are the first monoterpene trisindole alkaloids containing a vobasine–aspidosperma–aspidosperma skeleton [ 65 ]. Similarly, compound 233 is the first methylenedioxy dibromoindole alkaloid exhibiting antiosteoporosis activity [ 66 ]. Additionally, compound 234 is a dibrominated β-carboline sulfamate, one of the only 11 indole sulfamate-containing marine natural products reported in the Marin Lit.…”

“…Upon initial failure of a direct debromination of 5,6-methylenedioxyindole, they used an alternative reaction scheme containing three steps and obtained an overall yield of 56% ( Figure 18 ). The synthetic method also enabled the synthesis of 15 synthetic derivatives of compound 233 ( 294 to 308 ) for an SAR analysis ( Figure 19 ) [ 66 ]. The synthesis involved the reaction of 6-nitropiperonal ( 291 ) with NBS in concentrated H 2 SO 4 , producing 292 .…”

“…A Henry reaction (using Al 2 O 3 as a base and nitromethane) followed by dehydration using acetic anhydride transformed 292 into 293. However, since the latter was crystalline and hard to dissolve in many solvents, its crude mixture was reduced directly by an excess of iron in acetic acid, affording compound 233 [ 66 ].…”

“…Although compounds 305 and 306 had similar activities as 233 , compound 307 was less potent. Compound 308 , a tryptamine derivative, was more potent but was found cytotoxic at 25 μM, while none of the other derivatives showed toxicity even at 50 μM [ 66 ].…”

Marine natural products that inhibit osteoclastogenesis and promote osteoblast differentiation

“…Replacement of the bromines with chlorines significantly reduced activity. Evaluation of the potencies of N -acyl derivatives demonstrated that those with C 2 − C 8 -alkyl chains were equipotent or slightly more potent, but those with a C 14 -alkyl chain and benzoyl derivative were inactive even at 50 µM [ 53 ].…”