Outer-ring stereochemical modulation of cytotoxicity in cephalostatins.

[structure: see text] 20- and 25'-epimers of cephalostatin 7, prepared by directed unsymmetrical pyrazine synthesis, address outer-ring topographical and stability questions and intimate an oxacarbenium ion rationale for the role in bioactivity of the spiroketal (E/F, E'/F') rings of this class of antitumor agents.

On topography and functionality in the B-D rings of cephalostatin cytotoxins.

Analogues 12'beta-hydroxycephalostatin 1 (9), 7'-deoxyritterazine G (10), and 14-epi-7'-deoxyritterazine B (11) were prepared via our protocol for unsymmetrical pyrazine synthesis. Cytotoxicity against human tumors was also determined for the first time for ritterazines, with femtomolar potency and a high correlation to cephalostatins observed. The SAR of these and related compounds provide insight into the importance of topography and certain chemical functionality in the B-D and B'-D' rings of cephalostatin type antineoplastics.

On the relationship of OSW-1 to the cephalostatins.

Antineoplastic bis-steroidal (cephalostatin-type) analogues of the saponin OSW-1 were produced from a dihydroaglycone of OSW-1. The key aglycone 6H was obtained from 5alpha-androstan-3beta-ol-17-one in 8 steps (38% yield). The SAR of the aglycones, intermediates, and hybrid analogues provide insights regarding the proposed common role of C22-oxocarbenium ions in the bioactivity of both OSW-1 and cephalostatins.

Consequences of acid catalysis in concurrent ring opening and halogenation of spiroketals.

[formula: see text] Lewis and/or Bronsted acid additives permit ring opening and halogenation of spiroketals at substantially reduced temperatures to produce omega-iodo enol ethers in improved yield and purity, which can undergo further reaction in the presence of distal electrophilic centers to give new steroid skeletons.