New Cytotoxic Salinosporamides from the Marine Actinomycete Salinispora tropica

Abstract

An extensive study of the secondary metabolites produced by the obligate marine actinomycete Salinispora tropica (strain CNB-392), the producing microbe of the potent proteasome inhibitor salinosporamide A (1), has led to the isolation of seven related gamma-lactams. The most important of these compounds were salinosporamide B (3), which is the deschloro-analogue of 1, and salinosporamide C (4), which is a decarboxylated pyrrole analogue. New SAR data for all eight compounds, derived from extensive testing against the human colon carcinoma HCT-116 and the 60-cell-line panel at the NCI, indicate that the chloroethyl moiety plays a major role in the enhanced activity of 1.

Mutasynthesis of Fluorosalinosporamide, a Potent and Reversible Inhibitor of the Proteasome

“…[3][4][5] Besides the major analogue 2, S. tropica also accumulates the deschloro compound salinosporamide B (3), which is however at least two orders of magnitude less active against tumor cell lines. [6] This large difference in bioactivity is reflective of the respective mechanisms of the two compounds. With 2, after the drug becomes covalently tethered to the 20S proteasome by attack of the catalytic threonine residue on the electrophilic b-lactone unit, the resulting 3-hydroxy group displaces the 13-chloro group to yield an irreversibly bound adduct.…”

Advances toward the Synthesis of Functionalized γ-Lactams

“…4,8,10 Oxazolomycin A, neooxazolomycin, and lajollamycin are structurally similar to salinosporamide A (1, Figure 2). 49 The biological potential of these natural products has peaked interest in the synthetic community and several synthetic efforts have been reported. 48 Recent synthetic efforts towards 1 and oxazolomycins are described in this review.…”

Anticancer Antibiotics

“…An actinomycete, known as Salinispora, is found in tropical and subtropical marine sediments (Jensen and Mafnas 2006). Some species (like S. tropica) produce salinosporamides, which might be able to demonstrate proteasome inhibitor properties (Williams et al 2005). Salinosporamides share a γ-lactam-β-lactone bicyclic structure.…”