This communication describes the total synthesis of the marine polyether toxin, gambierol. This work couples our iterative C-glycoside/enol ether-olefin metathesis strategy to the subunits with a unique olefin metathesis/carbonyl olefination reaction to bring the subunits together.

Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG 2 -valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

Reactions of various diketo compounds with Deoxofluor [(CH(3)OCH(2)CH(2))(2)NSF(3)] have been investigated. When reacted with Deoxofluor, alpha-diketones, R(1)COCOR(2) (R(1) = R(2) = Ph; R(1) = R(2) = 4-Me-C(6)H(4); R(1) = Ph, R(2) = Me; R(1) = Me, R(2) = Et) (1a-d) formed difluoro derivatives (2a-d) in the presence of a catalytic amount of HF and/or tetrafluoro (3a-d) products depending on the reaction conditions and stoichiometry used. Reactions of beta-diketones, R(3)COCH(2)COR(4) (R(3) = R(4) = Ph; R(3) = R(4) = Me; R(3) = Me, R(4) = Ph) (4e-g), with Deoxofluor in the presence of a catalytic amount of HF led to the formation of difluoroalkenones as a mixture of E (5e-g) and Z (6e-g) isomers in good yield. Reaction of other diones, R(5)CO-X-COR(6) (R(5) = R(6) = Ph, X = -CH=CH-; R(5) = R(6) = Me, X = -C(6)H(4)C(6)H(4)-; R(5) = R(6) = Ph, X = -CH(2)CH(2)CH(2)-; R(5) = R(6) = Me, X = -CH(2)CH(2)-) (7h-k) with Deoxofluor produced mainly difluoro products (8h-k) with low yields of tertrafluoro derivatives (9h-k). Acyclic alpha-keto amides react poorly to give the corresponding difluoro derivatives, whereas cyclic alpha-keto amides (10l-p) react smoothly under very mild conditions to produce the corresponding difluoro products (11l-p) in >88% isolated yield.

A strategy for creating potent and pan‐genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U‐shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle‐bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan‐genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.

An expedient asymmetric total synthesis of aspidophytine is reported. A highly convergent strategy involving the sequential annulation of vinyl iodide 5 with indole 6 exploits varying modes of indole reactivity to provide aspidophytine in 23% over six steps from 5.