Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug Candidate

Abstract

The fungal-derived Taiwanese natural product antroquinonol A has attracted both academic and commercial interest due to its reported exciting biological properties. This reduced quinone is currently in phase II trials (USA and Taiwan) for the treatment of non-small-cell lung carcinoma (NSCLC) and was recently granted orphan drug status by the FDA for the treatment of pancreatic cancer and acute myeloid leukemia. Pending successful completion of human clinical trials, antroquinonol is expected to be commercialized under the trade name Hocena. A synthesis-enabled biological re-examination of this promising natural product, however, reveals minimal in vitro and in vivo antitumor activity in preclinical models.

11-Step Total Synthesis of Araiosamines

“…21 Scalable total syntheses have allowed us to identify natural products with erroneously reported potency. 22 This study, much akin to the axinellamines, 3c represents a rare case where natural products reported to lack biological activities have surfaced as antibacterial agents. Marine isolates like 1 , 3 , and 4 are difficult to isolate or grow in a cell culture.…”

Synthesis of (+)‐Antroquinonol and Analogues by Using Enantioselective Michael Reactions of Benzoquinone Monoketals

“…Although we were able to repeat the previously reported Michael reaction of 4,4‐dimethoxycyclohexa‐2,5‐dien‐1‐one by using Me 2 Zn, Cu(OTf) 2 , and chiral ligand ( S , R , R )‐ B to obtain the desired conjugate addition product ( R )‐3‐methyl‐4,4‐dimethoxycyclohex‐2‐en‐1‐one in 72 % yield with 99 % ee , the enantioselective Michael reaction of 2a was problematic, because the four electron‐donating methoxy substituents make 2a a poor Michael acceptor toward a nucleophilic reagent . The similar problem of reluctant Michael reactions of highly electron‐rich system has also been encountered by the Baran and Chen groups , …”

“…[ α ] D 25 = +45.0 ( c = 0.48, CHCl 3 ); ref . [ α ] D 18 = +72.7 ( c = 0.28, CHCl 3 ); ref . [ α ] D 20 = +52.0 ( c = 0.364, MeOH); ref .…”

“…In contrast, our first‐generation synthesis of (±)‐antroquinonol and (±)‐antroquinonol D only requires six steps and uses Michael reactions of the appropriate benzoquinone monoketals with a dimethylcuprate reagent as the strategic key step . In our preliminary study, we indicated that the asymmetric Michael addition of 3,4,4‐trimethoxycyclohexadienone with a methylmetal reagent could be carried out and that the 1,4‐adduct could be elaborated through a similar procedure to give optically active antroquinonol D. Recently, Dhar, Baran, and co‐workers examined many routes to synthesize (+)‐antroquinonol but found the asymmetric Michael reaction of the appropriate benzoquinone monoketal as the only viable method . Their report has prompted us to disclose our independent research on the enantioselective Michael reactions of benzoquinone monoketals 2a – 2j (Tables and ), which is a continuation of our previous studies and can be applied to the syntheses of (+)‐antroquinonol and (+)‐antroquinonol D (Scheme ).…”

Development of a Cross‐Conjugated Vinylogous [4+2] Anionic Annulation and Application to the Total Synthesis of Natural Antibiotic (±)‐ABX

“…In those cases, further dehydrogenation with a stronger oxidant DDQ rather than mild dry air (O 2 ) was required to reach the final aromatized products as exemplified with adducts 15-17, 23, and 34. Some Michael acceptors highlighted in green in adducts 11, 18,26,27,32,38, and 42 are quinone monoketals, which have been known to possess redox activity, [14] and could play dual functions to provide both desired and redox products. Taking acceptor 43 as an example (Scheme 3 a), when it was coupled with donor 5 under standard conditions, the regular product 11 was formed in 51 % yield accompanied with a redox product 44 in 44 % yield.…”