Chemistry of Trisdecacyclic Pyrazine Antineoplastics: The Cephalostatins and Ritterazines † This review is dedicated to the community of isolation/identification natural product detectives, with special thanks to the groups of Bob Pettit and Nobuhiro Fusatani.

NMR Characterization and Crystal Structure of 22-Phenyl-3β-acetoxy-bisnorchol-5-en-22-one

“…In addition to their intrinsic biological activity, many naturally occurring steroids have been employed as starting materials for the synthesis of bioactive compounds that include drugs [1], ecdysteroids [2], citotoxic steroids [3][4][5], and plant growth promoting substances [6][7][8].…”

The Cephalostatins. 22. Synthesis of Bis-steroidal Pyrazine Pyrones

“…Subsequently, 1 became the prototype of the cephalostatins 2 and ritterazines, which together make up a unique family of 45 highly oxygenated bis-steroidal pyrazines. 3 These marine invertebrate constituents exhibit powerful cancer cell growth inhibitory behavior (e.g., murine P388 lymphocytic leukemia cell line, ED 50 10 −7 µg/mL; NCI 60 human cancer cell lines, GI 50 1.8 nM). 2 The availability of the cephalostatins and ritterazines from their only known natural sources, C. gilchristi and the marine tunicate Ritterella tokioka , is still extremely limited.…”

“…By 1998, Fuchs and colleagues had completed the first total synthesis of 1 (in 65 synthetic steps) 4a and of two additional members of the cephalostatin family (7 and 12) and ritterazine K. 4b However, owing to the complexity of the targets only very small amounts of these substances were produced and in very low overall yields (2 mg of 1 , 10 −5 %, for instance), 4a not suitable to supply sufficient samples at reasonable cost for extended biological evaluation. However, the recent enantioselective total synthesis of cephalostatin 1 by Shair 3c does offer a potentially useful approach to scale-up and represents a splendid contribution. Meanwhile, a number of SAR studies concerned with the cephalostatins were initiated by various research groups in an effort to discover the minimum pharmacophore required to maintain potent cancer cell growth inhibitory behavior.…”

“…The urgency of the practical syntheses and structural simplification endeavor was elevated when Vollmar and colleagues 3e,7 began to elucidate the unique mechanism of cephalostatin 1 ( 1 ). Because of their detailed research results, it is clear that 1 evokes a new cytochrome c -independent apoptosis signaling pathway.…”

Synthesis and Evaluation of a Fluorescent Ritterazine–Cephalostatin Hybrid

“…This potent activity along with their unique cell selectivity and apoptotic response has drawn attention to their potential as clinical leads for cancer. 2 …”