A palladium catalyzed, carbon monoxide mediated, double reductive cyclization of 1,4-, 1,3-, and 2,3-bis(2-nitroaryl)-1,3-butadienes to afford 2,2'-, 2,3'-, and 3,3'-biindoles, respectively, was developed. In contrast, reductive cyclizations of 1,2-bis(2-nitroaryl)ethenes were nonselective, affording mixtures of monocyclized indoles, indolo[3,2-b]indole, indolo[1,2-c]quinazolin-6(5H)-ones, and 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones. Nonselective product formation was also observed from reductive cyclization of 1,1-bis(2-nitroaryl)ethenes, producing indolo[2,3-b]indoles and indolo[2,3-c]quinolin-6-ones. Carbon monoxide insertion to give the carbonyl containing products was the major or sole reaction path starting from 1,1- or 1,2-bis(2-nitroaryl)ethenes.

Expedient syntheses of the indole alkaloids alocasin A, scalaridine A, and hyrtinadine A-B are presented. All four natural products contain one or two 5-hydroxyindolyl units. Three palladium catalyzed reactions, an alkyne hydrostannylation, a Kosugi-Migita-Stille cross coupling and a reductive N-heterocyclization are the key steps in the syntheses. Introduction Several bisindole alkaloid metabolites such as hamacanthins, 1 dragmacidins, 2 topsentins (spongetins), 1a-b, 1e, 3 nortopsentins, 4 and rhopaladins 5 have been isolated from marine sponges and tunicates. 6 These metabolites exhibit diverse bioactivities such as cytotoxic, 1b, 1g, 2d, 3a, 4 antiviral, 1g, 2b, 4 antifungal, 7 antibacterial, 7 and antiplasmodial 8 activities. The common feature of all these alkaloids is the presence of an imidazole/pyrazinone (or a reduced derivative) linker either attached directly to the 3 positions of the two indoles or attached via a carbonyl carbon and/or methine. In addition to a heterocyclic linker, the indole fragments are usually brominated in one or both of the 6 positions. Hydroxylation in the 6 or 7 position can also be found in some of the metabolites.

Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with K i values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.

The naturally occurring polybrominated indoles 2,2′,5,5′-tetrabromo-3,3′-bi-1H-indole, 2,2′,6,6′-tetrabromo-3,3′-bi-1H-indole, and 2,2′,5,5′,6,6′-hexabromo-3,3′-bi-1H-indole were synthesized using a palladium catalyzed, carbon monoxide mediated, double reductive N-heterocyclization of 2,3-bis(2-nitro-4(or 5)-bromophenyl)-1,4-butadienes as the key step.

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