Using this combinatorial library approach, a family of potent 2,2-dimethylbenzopyran-based inhibitors was developed with IC(50) values in the range of 18-55 nM. Cell-based assays revealed that these inhibitors were rather non-cytotoxic in the MCF-7 cell line; however, they were quite cytostatic in a panel of cancer cell lines suggesting their potential as chemotherapeutic/chemopreventive candidates.

Psammaplin A is a symmetrical bromotyrosine-derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Among the most active leads derived from these studies are compounds 104, 105, 113, 115, 123, and 128. The present, catalytically-induced, disulfide exchange strategy may be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.

In the preceding Communication in this issue [1] we described the total synthesis of a potential decalin precursor to azadirachtin (1), [2] its coupling to a suitable norbornene fragment 4 (Scheme 1), and the elaboration of the product to an advanced intermediate along the path to this synthetic target. Herein we report the total synthesis and semisynthesis from azadirachtin of a more advanced decalin system 3, its coupling to the same norbornene fragment 4, and the elaboration of the resulting product to an advanced intermediate for the total synthesis of azadirachtin (Scheme 1). This report also includes a number of unusual reactions induced by proximity effects and special steric factors highlighting the unique characteristics of the azadirachtin scaffold.Having successfully synthesized tricyclic decalin system 5, (Scheme 1) and explored its chemistry toward azadirachtin (1) as described in the preceding Communication, [1] we turned our attention to the more advanced tetracyclic decalin precursor 3, which bears the tetrahydrofuran ring system of 1 within its structure. Our plan to synthesize the targeted intermediate 3 required key building block 6 (Scheme 2) as