A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.

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MAREK MAJEWSKI AND GUO-ZHU ZHENG. Can. J. Chem. 70, 261 8 (1992). Tropinone (6) was deprotonated with lithium diisopropylamide and with chiral lithium amides (18)(19)(20)(21)(22)(23)(24) and the resulting enolates (two enantiomers) were treated with electrophiles. The aldol reaction with benzaldehyde and deuteration were both diastereoselective. The former yielded only one isomer (exo, anti) of the aldol 8a; the latter proceeded from the exo face. This selectivity permitted us to probe the deprotonation of tropinone with lithium amides; it was concluded that the reaction involves predominantly the exo axial protons. The reaction of tropinone enolate with ethyl chloroformate led, via a ring opening, to the cycloheptenone derivative 9. The reaction with methyl cyanoformate yielded, in the presence of silver acetate and acetic acid, the P-ketoester 8b; however, in the absence of these additives, and especially when 12-crown-4 was added to the enolate, a ring opening leading to the pyrrolidine derivative 10 occurred instead. Deprotonation of tropinone with chiral lithium amides proceeded with modest enantioselectivity. A synthesis of non-racemic anhydroecgonine via this strategy allowed establishing the absolute stereochemistry of deprotonation.MAREK MAJEWSKI et Guo-ZHU ZHENG. Can. J. Chem. 70, 2618Chem. 70, (1992 On a dtprotonk la tropinone (6) a l'aide du diisopropylamidure de sodium et des amidures de lithium chiraux (18-24) et l'on a trait6 les Cnolates qui se sont formts (deux knantiomkres) avec des klectrophiles. La reaction aldolique avec le benzaldkhyde ainsi que la deuttration sont toutes les deux diastkrkosClectives; la premikre ne fournit qu'un isomtre (exo, anti) de l'aldol 8a alors que la dernikre se produit par la face exo. Cette sklectivitt a permis d'examiner la dtprotonation de la tropinone avec des amidures de lithium; on en a conclu que la rtaction implique principalement les protons axiaux exo. La rkaction de l'knolate de tropinone avec le chloroformate d'kthyle conduit, par le biais d'une ouverture de cycle, au dCrivC cycloheptknone 9. La rtaction avec le cyanoformate de mtthyle, rkaliste en presence d'acttate d'argent et d'acide acCtique, conduit au p-cCtoester 8b; toutefois, lorsque cette addition est rtaliste en l'absence de ces additifs et particulikrement lorsqu'on ajoute de l'Cther 12-couronne-4 21 l'knolate, il se produit plut6t une ouverture de cycle conduisant au dtrivt de la pyrrolidine 10. La dkprotonation de la tropinone sous I'influence d'amidures de lithium se produit avec une knantiosklectivitt modeste. Une synthkse de I'anhydroecgonine non-rackmique a l'aide de cette stratCgie a permis d'ktablir la stCrtochimie absolue de la dkprotonation.[Traduit par la rkdaction] Introduction strategy suitable for the construction of a number of tropane alkaloids (6) in a stereoselective manner.

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Mutations in the ligand-binding domain of estrogen receptor alpha (ERα) are detected in up to 30% of patients (pts) who have relapsed or progressed during endocrine therapy. By favoring the agonistic conformation in ERα, these hotspot mutations promote ligand-independent activation of ERα and confer partial resistance to ER-directed therapies. Of the various hotspot mutations, Y537S is the most constitutively active, promotes the greatest resistance phenotype to current endocrine therapies, and is associated with the worst prognosis relative to other ERα mutations. The fact that current ER-directed therapies have limited activity in the ERα mutant setting emphasizes the critical need to develop the next generation of high affinity ER antagonists that can overcome the aberrant activity of mutant ERα. H3B-6545 is a first-in-class selective ERα covalent antagonist (SERCA) which inactivates both wild-type and mutant ERα by irreversibly engaging cysteine-530. Biophysical and biochemical analyses confirm the long residence time achieved by covalent binding, and cellular analyses confirm the selectivity and single-digit nanomolar potency of H3B-6545 across a panel of ERαWT and ERαMUT breast cancer cell lines. H3B-6545 as a monotherapy demonstrates superior anti-tumor activity relative to fulvestrant across a set of CDK4/6 inhibitor naïve ERαWT and ERαY537S cell line-derived xenograft (CDX)/patient-derived xenograft (PDX) models, with regressions being noted in both the ERαWT and ERαMUT settings. Furthermore, H3B-6545 continues to demonstrate single agent activity in CDK4/6 inhibitor-resistant ERαWT and ERαY537S PDX models, in which fulvestrant fails to demonstrate significant anti-tumor activity. Lastly, improved activity and duration of response are noted when H3B-6545 is combined with several targeted therapies, including CDK4/6 inhibitors palbociclib and abemaciclib across a range of ERαWT and ERαY537S CDX/PDX models. The phase I-II trial (NCT03250676) enrolled 130 heavily pretreated pts with ER+, HER2- metastatic breast cancer, including 12 pts harboring high allele frequency clonal ESR1 Y537S circulating tumor DNA (ctDNA). Median number of prior therapy in the metastatic setting was 3 (range: 1-10). Consistent with the preclinical data, H3B-6545 demonstrated promising clinical activity among these pts with clonal Y537S mutations, with a median progression free survival of 7.3 months and an overall response rate of 25% (3 confirmed partial responses). In summary, these compelling preclinical data coupled with emerging clinical activity in heavily pretreated poor prognosis pts support further development of H3B-6545 as monotherapy or combination treatment. Citation Format: Manav Korpal, Craig Furman, Xiaoling Puyang, Zhaojie Zhang, Zhenhua Wu, Deepti Banka, Subhasree Das, Benoit Destenaves, Lei Gao, Erika Hamilton, Ming-Hong Hao, Sean Irwin, Stephen Johnston, Jaya J Joshi, Dejan Juric, Amy Kim, Tuong-Vi Nguyen, Marc Pipas, Timothy Pluard, Victoria Rimkunas, Nathalie Rioux, Joanne Schindler, Peter Smith, Michael Thomas, John Wang, Judy S Wang, Markus Warmuth, Huilan Yao, Shihua Yao, Lihua Yu, Frédéric H Vaillancourt, David M Bolduc, Nicholas A Larsen, GuoZhu Zheng, Sudeep Prajapati, Tarek Sahmoud, Antonio Gualberto, Ping Zhu. Development of H3B-6545, a first-in-class oral selective ER covalent antagonist (SERCA), for the treatment of ERaWT and ERaMUT breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-23.

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