Salinispora tropica

Salinosporamide A (84), a y-lactam alkaloid isolated from marine actinomycete Salinispora tropica also proved to possess strong antimalarial activity both in vitro (IC50 11.4 nM) and in vivo ... 

Williams PG, Buchanan GO, Fehling RH, Kauffman CA, Jensen PR, Fenical W (2005) New Cytotoxic Salinosporamides from the Marine Actinomycete Salinispora tropica. J Org Chem 70 6196... 

Reed KA, Manam RR, Mitchell SS, Xu J, Teisan S, Chao T-H, Deyanat-Yazdi G, Neuteboom STC, Lam KS, Potts BCM (2007) Salinosporamides D-J from the Marine Actinomycete Salinispora tropica, Bromosalinosporamide, and Thioester Derivatives Are Potent Inhibitors of the 20S Proteasome. J Nat Prod 70 269... 

Organism Streptomyces coelicolor A3(2)40 S. griseus IFO 1335042 Salinispora tropica CNB-4405 Mycobacterium tuberculosis H37Rv43 Frankia sp. CcI344 N. farcinica IFM 1015245... 

Udwary DW, Zeigler L, Asolkar RN, Singan V, Lapidus A, Fenical W, Jensen PR, Moore BS (2007) Genome Sequencing Reveals Complex Secondary Metabolome in the Marine Acti-nomycete Salinispora tropica. Proc Natl Acad Sci USA 104 10376... 

Salinosporamides Salinispora tropica Inhibitors of proteasome function and cytotoxic activity (tumor cells)... 

Udwary DW, et al. Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc. Natl. Acad. Sci. U.S.A. 2007 104 10376-10381. Edwards DJ, et al. Structure and biosynthesis of the ja-maicamides, new mixed polyketide-peptide neurotoxins from the marine cyanobacterium Lyngbya majuscula. Chem. Biol. 2004 11 817-833. 

Recent pursuit of marine microbial sources led to the isolation of salinosporamide A (83). It is a P-lactone produced by the marine bacteria Salinispora tropica and is a proteasome inhibitor (86). Mechaiustically, it works by specific covalent modification of the target. This compound has entered human cliiucal development for treatment of multiple myeloma (87-89). 

Salinosporamide A, NPI 0052, a microbial product of Salinispora tropica strain CNB-392 that acts as a potent protea-some inhibitor. Salinosporamide A is structurally related to omuralide, the -lactone derived from lactacystin, and is more effective as a proteasome inhibitor than omuralide. Furthermore, it exhibits cytotoxicity against many tumor cell lines, especially against Velcade resistant multiple myeloma cells [V. Caubert, N. Langlois, Tetrahedron Lett. 2007, 48, 381]. 

Udwary, D. W., Zeigjer, L., Asolkar, R. N., Singan, V., Lapidus, A., Fenical, W., Jensen, P. R., Moore, B. S. Genome sequencing reveals comples secondary metabolome in the marine actinomycete Salinispora tropica. Proc. Natl. Acad ScL USA 2007,104,10376—10381. 

Sporolides A and B were isolated in 2005 from a fermentation broth of a strain of the marine actinomycete Salinispora tropica. The structures 377 and 378 and the absolute stereochemistries for sporolide A and sporolide B were elucidated using a combination of NMR spectroscopy and X-ray crystallography. Unformnately, the sporolides, tested for antitumor and antibacterial activity, were inactive (Figure 3.130) [470]. 

Salinosporamides are a family of y-lactam-p-lactone natural products discovered in 2003 with the isolation of salinosporamide A from Salinispora tropica obtained from marine sediment from the Bahamas and from depths as great as -1100 m. The complete structural assignment 86 to salinosporamide A was accomplished by spectral analysis and by a single-crystal X-ray diffraction study (Figure 4.41) [207]. The pronounced anticancer activity of 86, as a 20S proteasome inhibitor, with IC50 values... 

Figure 4.45 (a) Schematic representation of the organization of the sal biosynthetic gene cluster from Salinispora tropica strains CNB-476 and CNB-440. (b) Proposed mechanism of salinosporamide assembly by the PKS-NRPS machinery SalA-SalB. 

Recent application of PKSE data sets and the noted PCR-based strategy has revealed that the biosynthetic gene cluster for sporolides A and B contains two loci encoding PKSEs 13). Produced by Salinispora tropica, sporolides A and B do not contain enediynes per se (Figure Ic). Rather, each substance contains a tricyclic motif that is proposed to originate biosynthetically from a transient... 

Proteasome inhibitors receive widespread attention as promising treatment options in cancer chemotherapy. One of the most promising drug candidates of this class is saUnosporamide A (53), isolated from the marine bacterium Salinispora tropica (Fig. 15.3) [54], The densely functionalized y-lactam-p-lactone pharmacophore is responsible for its irreversible binding to the p subunit of the 20S proteasome [55]. Moore et al. reported a biosynthetic synthesis of antipro-tealide (52) and were furthermore able to generate other nonnatural salinosporamide derivatives 54 with C-5 modifications... 

SCHEME 15.17 Fluorosalinosporamide engineering approach (top) and biosynthesis of salinosporamide A by Salinispora tropica (bottom)... 

Eustaquio AS, O Hagan D, Moore BS. Engineering fluoro-metabolite production Fluorinase expression in Salinispora tropica yields fluorosalinosporamide. J. Nat. Prod. 2010 73 378-382. 

Salinispora tropica (N PI-0052) Sediment (-1 m) Bahamas Sporolides Salinosporamides A-C Salinosporamides D-j Anti proteal ide Cytotoxics, inhibitors of proteasome Buchanan et al., 2005 Williams et al., 2005 Beer eto/., 2007 Reed et al., 2007 Udwaryeto/., 2007 Manam et al., 2009... 

Feling et al, 2003 Macherla etal, 2005a Groll et al, 2006 Salinosporamide B (R = H) Salinispora tropica Williams ( /., 2005 Beer Moore, 2007... 

Salinosporamide F (R = Cl) Slsomlcin Salinosporamide G(R = H) Streptomyces sp. Salinispora tropica Lu etaL, 2009... 

Buchanan, G,0 Williams, P,G Feling, R.H., Kauffman, C.A, Jensen, P.R., and Fenical, W, (2005) Sporolides A and B Structurally unprecedented halogenated macrolides from the marine actinomycete Salinispora tropica. Org. Lett., 7, 2731-2734. 

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