10232. Salinosporamides

Description and references

Family of cytotoxic proteasome inhibitors produced by the marine actinomycete, Salinispora tropica. Characterized by a fused γ-lactam-β-lactone ring structure; salinosporamide A is the most abundant. Isoln, structure, and bioactivity of A: R. H. Feling et al., Angew. Chem. Int. Ed. 42, 355 (2003) DOI PubMed; W. Fenical et al., US 7176232 (2007 to Regents of Univ. Calif.). Isoln of B and C: P. G. Williams et al., J. Org. Chem. 70, 6196 (2005) DOI PubMed; of D-J: K. A. Reed et al., J. Nat. Prod. 70, 269 (2007) DOI PubMed. Total syntheses of A: L. R. Reddy et al., J. Am. Chem. Soc. 126, 6230 (2004) DOI PubMed; A. Endo, S. J. Danishefsky, ibid. 127, 8298 (2005) DOI PubMed. Structure-activity study: V. R. Macherla et al., J. Med. Chem. 48, 3684 (2005) DOI PubMed. Pharmacology and antitumor activity of A: D. Chauhan et al., Cancer Cell 8, 407 (2005) DOI PubMed. Biosynthetic studies: G. Tsueng et al., Appl. Microbiol. Biotechnol. 75, 999 (2007) DOI PubMed; L. L. Beer, B. S. Moore, Org. Lett. 9, 845 (2007) DOI PubMed.

Chemical structure

Derivative

Salinosporamide A.

Nomenclature

CAS number: 437742-34-2
(1R,4R,5S)-4-(2-Chloroethyl)-1-[(S)-(1S)-2-cyclohexen-1-ylhydroxymethyl]-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione; NPI-0052.
C15H20ClNO4; mol wt 313.78.
C 57.42%, H 6.42%, Cl 11.30%, N 4.46%, O 20.40%.

Description and references

Soly and degradation study: N. Denora et al., J. Pharm. Sci. 96, 2037 (2007) DOI PubMed.

Properties

Colorless needles from ethyl acetate/iso-octane, mp 169-171°. [α]D25 72.9° (c = 0.55 in CH3OH). pKa 3.93. uv max (methanol): 225, 205 nm (log ε 3.3, 4.03). Sol in chloroform, methanol, DMSO, acetone, acetonitrile, benzene, pyridine, DMF. Soly in aq sodium acetate buffer (pH 5): 35.3±0.9 μg/ml.

Derivative

Salinosporamide B.

Nomenclature

CAS number: 863126-95-8
(1R,4R,5S)-1-[(S)-(1S)-2-Cyclohexen-1-ylhydroxymethyl]-4-ethyl-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione; NPI-0047.
C15H21NO4; mol wt 279.33.
C 64.50%, H 7.58%, N 5.01%, O 22.91%.

Properties

Amorphous crystals from ethyl acetate, mp 143-145°. [α]D 54.5° (c = 0.286 in CH3OH). uv max (methanol): 256 nm (log ε 3.7).

Derivative

Salinosporamide C.

Nomenclature

CAS number: 863126-96-9
(4aR,8aS,9S,9aR)-2-(2-Chloroethyl)-4a,7,8,8a,9,9a-hexahydro-9-hydroxy-1-methyl-3H-pyrrolo[1,2-a]indole-3,6(5H)-dione.
C14H18ClNO3; mol wt 283.75.
C 59.26%, H 6.39%, Cl 12.49%, N 4.94%, O 16.92%.

Properties

Colorless oil. [α]D 33.6° (c = 0.268 in CH3OH). uv max (methanol): 222 nm (log ε 3.9).