A three-component coupling approach to the marine bis-indole alkaloids: Topsentin, deoxytopsentin and bromotopsentin

Marine Bi-, Bis-, and Trisindole Alkaloids

“…26 While optical rotation data were reported by Bao et al in their later paper, the absolute configuration of 55 had not been established. 26,32 The closely related bisindole imidazoles, nortopsentins A, B, and C (48)(49)(50), were first reported in 1991 by Sakemi and Sun,39 together with known compounds 43 and 44 from the same Caribbean Spongosorites investigated by Tsujii et al 25,39 Interestingly, they reported not seeing doubling of NMR signals due to slow tautomeric interconversion, which suggests either a rapid proton transfer reaction relative to the topsentins or, alternatively, none at all. Sakemi et al postulated that the N-1 proton on the imidazole ring in topsentins and spongotines undergoes hydrogen bonding with the 2-acyl functionality, hence slowing down proton exchange and possibly rotation, resulting in NMR signal duplication.…”

“…3 While in previous studies, 4,5-dihydrotopsentins have been shown to be inactive against S. aureus strains, 3,10 and 44 had shown marginally greater antibacterial activity than 47, 27,33 Zoraghi et al 3 reported that 44 was inactive in both the PK inhibition assays and against two S. aureus strains including one MRSA strain. While both 47 and 52 inhibited MRSA PK, 52 was a more active inhibitor of MRSA PK (IC 50 60 nM) compared to the known MRSA PK inhibitor NSK5-15 (IC 50 185 nM) including a 166-fold greater inhibition selectivity of MRSA PK compared with human PK isoforms. 3 Finally, 42 and 48 were tested against a chloroquine-resistant strain of Plasmodium falciparum with 48 displaying good activity (IC 50 0.46 mM) compared with 42 (IC 50 10.3 mM).…”

“…While both 47 and 52 inhibited MRSA PK, 52 was a more active inhibitor of MRSA PK (IC 50 60 nM) compared to the known MRSA PK inhibitor NSK5-15 (IC 50 185 nM) including a 166-fold greater inhibition selectivity of MRSA PK compared with human PK isoforms. 3 Finally, 42 and 48 were tested against a chloroquine-resistant strain of Plasmodium falciparum with 48 displaying good activity (IC 50 0.46 mM) compared with 42 (IC 50 10.3 mM). 45 …”

“…13 L. brongniartii collected off the southern tip of Taiwan yielded a further two related thioether-and sulfoxide-substituted biindoles 9 and 10 with only compound 10 displaying optical activity 14 (Figure 1.2). Biindole 10 was reported to be cytotoxic against the P338 and HT-29 cancer cell lines; however, no IC 50 Finally, a Dictyodendrilla sp. sponge also collected off Okinawa yielded a C 2 symmetrical biindole, dendridine A (11) 15 (Figure 1.2).…”

“…15 Although Tsuda et al 15 commented on the rarity of naturally occurring 7-hydroxyindoles, this substitution pattern is commonly encountered in many dragmacidin bisindoles. 4 Dendridine A exhibited inhibitory action against two gram-positive bacteria Bacillus subtilis (IC 50 8.3 mg/mL) and Micrococcus luteus (IC 50 4.2 mg/mL) and the fungus Cryptococcus neoformans (IC 50 8.3 mg/mL) in addition to weak cytotoxicity against murine leukemia L1210 cells (IC 50 32.5 mg/mL). 15 …”