Stereocontrolled radical cyclization reactions to yield exocyclic alkenes

The intramolecular reactions of a number of (E)- and (Z)-3-tri(n-butyl)stannyl-2-alkenoates with ω-alkyl radicals generated from alkyl iodides, epoxides, and aldehydes were investigated. These reactions were found to generate exocyclic alkenes in a stereoselective, and in some cases stereospecific, manner via a consecutive radical addition-fragmentation mechanism. In most cases, the geometry of the resulting exocyclic alkene was determined by the geometry of the starting vinylstannane. For example, reaction of the (E)-vinylstannane 75 with bis(cyclopentadienyl)titanium(III) chloride affords the (E)-exocyclic alkene 82 exclusively, whereas the analogous reaction of the (Z)-vinylstannane 76 affords the (Z)-exocyclic alkene 83 as the exclusive product. The formation of exocyclic alkenes via intramolecular addition reactions of secondary alkyl radicals to α,β-alkynyl esters was also investigated. The stereoselectivity of these reactions was found to be highly dependent on the reaction conditions. For example, reaction of 146 with tri(n-butyl)tin hydride in refluxing benzene affords predominantly the (E)-exocyclic alkene 142. In contrast, reaction of 146 with tris(trimethylsilyl)silane at low temperature affords predominantly the (Z)-exocyclic alkene 144. [ Formulas omitted ]Science, Faculty ofChemistry, Department ofGraduat

Abstract 2894: XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma

Abstract The Dolasynthen platform incorporates the highly potent anti-mitotic agent auristatin F-HPA (AF-HPA), with its associated DolaLock mechanism of controlled bystander effect, and enables the synthesis of antibody-drug conjugates (ADCs) with precise control of the drug-to-antibody ratio (DAR) and site-specific bioconjugation. XMT-1592 is a novel ADC comprised of an anti-NaPi2b antibody and Dolasynthen, conjugated in a site-specific manner to yield DAR 6. NaPi2b, also known as SLC34A2, is a transmembrane sodium-phosphate transporter that is broadly expressed on tumor cells in ovarian carcinoma, NSCLC lung adenocarcinoma and other tumor types. Recent studies have shown that NaPi2b expression is enriched in the EGFR and KRAS mutant subtypes of lung adenocarcinoma. Binding studies showed a specific, high-affinity interaction of XMT-1592 with NaPi2b that was not affected by conjugated Dolasynthen. XMT-1592 elicited potent and specific in vitro cytotoxicity against NaPi2b-expressing ovarian carcinoma cells. XMT-1592 exhibited potent and specific in vivo activity in NaPi2b-expressing tumor xenografts derived from ovarian carcinoma or lung adenocarcinoma. Consistent with the targeted delivery benefits of the ADC approach, XMT-1592 yielded high and sustained concentrations of AF-HPA to tumors but not normal tissues. To evaluate the benefits of site-specific bioconjugation of Dolasynthen, we conducted in vitro and in vivo comparisons of XMT-1592 to a stochastically conjugated version of the ADC. XMT-1592 had improved in vivo activity, pharmacokinetics, and clinical pathology relative to its stochastic counterpart. Taken together, these results support XMT-1592 as a development candidate for the treatment of NaPi2b-expressing tumors. Citation Format: Shawn Fessler, Anouk Dirksen, Scott D. Collins, Ling Xu, Winnie Lee, Jason Wang, Ron Eydelloth, Elena Ter-Ovanesyen, Jeffrey Zurita, Elizabeth Ditty, Barrett Nehilla, Susan Clardy, Susan Clardy, Tyler Carter, Kenneth Avocetien, Mark Nazzaro, Nam Le, Kalli C. Catcott, Alex Uttard, Bingfan Du, Chen-Ni Chin, Rebecca Mosher, Kelly Slocum, Liuliang Qin, David Lee, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2894

Table S3 from Development of a Novel DNA Mono-alkylator Platform for Antibody–Drug Conjugates

Table shows Payload in vitro potency in various cell lines.</p

Figure S8 from Development of a Novel DNA Mono-alkylator Platform for Antibody–Drug Conjugates

Figure shows Cytotoxicity of Mesothelin ADCs M-16, M-17, and M-19 in NCI-N87 cell line</p

Figure S7 from Development of a Novel DNA Mono-alkylator Platform for Antibody–Drug Conjugates

Figure shows Efficacy in OVCAR-3 xenograft for A) targeted ADCs X-17 and X-19 and B) their corresponding non-binding control ADCs NB-17 and NB-19</p