Design and Synthesis of 12‐Aza‐Epothilones (Azathilones)—“Non‐Natural” Natural Products with Potent Anticancer Activity

Abstract

Improving on nature: Azathilones 1 a and 1 b are “non‐natural” natural products derived from epothilones through C→N exchange at position 12. They are highly potent inducers of tubulin polymerization (part of a microtubule is shown in the picture) and inhibit human cancer cell growth in vitro. These compounds present a new structural scaffold for microtubule stabilization and are promising lead structures for anticancer‐drug discovery.

Selected hybrid natural products as tubulin modulators

“…Another compound F3.4, having a trans epoxide in F3.2 was also synthesized. In another study, to obtain novel hybrids of epothilones, they designed C12 aza-epothilones by substituting C12 with "nitrogen atom" (F3.5), and the other common side chain benzimidazole (F3.6) [17]. The structural features of these derivatives (Fig.…”

Epothilones: From Discovery to Clinical Trials

“…12–13-desoxy derivatives show increased activity, better pharmacokinetics and bioavailability; 10,44,54 methyl group in 12 increases activity over hydrogen; C12 substituents larger than methyl group (ethyl, propyl, acetal cyclohexyl) are tolerated; 51 C12–C13 oxazoline bridged are tolerated; 82 rigidified and C10–C12 bridged derivatives are inactive; 82 derivatives containing nitrogen in position 12 (azathilones) are tolerated; 67,84 C12–C13 cyclopropyl derivatives are tolerated.…”

“…Substituents containing aromatic groups are essential in C15; 51,62 chirality of C15 is essential; aromatic groups attached directly to C15 are not tolerated; 53,62 oxazole and pyridine rings tolerated; 40,64 heterocycles fused with C27 (benzimidazole, benzothiazole, quinoline) are tolerated; 53,84 bulky groups attached to C27 are not tolerated; position of hydrogen-bond acceptor atoms in heterocycles is important; 53,85 substituents attached to C21 are tolerated. 85 …”

The Epothilones: An Outstanding Family of Anti-Tumor Agents

“…References, pp. [126][127][128][129][130][131][132][133] which was converted to phenyl ester 186 via a novel Baeyer-Villiger oxidation, catalyzed by diamide 185. In three additional steps ketone 187 was prepared, which was the coupling partner of 9 and 10 to give the 2a-precursor 188 and the 2b-precursor 189 (Chart 35).…”