Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect.

Antibody-drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.

Total Synthesis and Biological Evaluation of Tiancimycins A and B, Yangpumicin A, and Related Anthraquinone-Fused Enediyne Antitumor Antibiotics.

The family of anthraquinone-fused enediyne antitumor antibiotics was established by the discovery of dynemicin A and deoxy-dynemicin A. It was then expanded, first by the isolation of uncialamycin, and then by the addition to the family of tiancimycins A-F and yangpumicin A. This family of natural products provides opportunities in total synthesis, biology, and medicine due to their novel and challenging molecular structures, intriguing biological properties and mechanism of action, and potential in targeted cancer therapies. Herein, the total syntheses of tiancimycins A and B, yangpumicin A, and a number of related anthraquinone-fused enediynes are described. Biological evaluation of the synthesized compounds revealed extremely potent cytotoxicities against a number of cell lines, thus enriching the structure-activity relationships within this class of compounds. The findings of these studies may facilitate future investigations directed toward antibody-drug conjugates for targeted cancer therapies and provide inspiration for further advances in total synthesis and chemical biology.

Metal-Controlled Switching of Enantioselectivity in the Mukaiyama-Michael Reaction of α,ß-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Metal-Pybox Complexes.

Metal-directed switching of enantioselectivity in the Mukaiyama-Michael reaction of silyl enol ethers to α,ß-unsaturated 2-acyl imidazoles using the same chiral indapybox ligand has been reported. The utility of this approach has been portrayed in the synthesis of both enantiomers of optically active δ-keto acid and ester as well as 3,4-dihydropyran-2-one. Moreover, enantioswitching in the construction of the tertiary stereocenter adjacent to a gem-dimethyl group has been achieved.

Rapid discovery and evolution of nanosensors containing fluorogenic amino acids.

Binding-activated optical sensors are powerful tools for imaging, diagnostics, and biomolecular sensing. However, biosensor discovery is slow and requires tedious steps in rational design, screening, and characterization. Here we report on a platform that streamlines biosensor discovery and unlocks directed nanosensor evolution through genetically encodable fluorogenic amino acids (FgAAs). Building on the classical knowledge-based semisynthetic approach, we engineer ~15 kDa nanosensors that recognize specific proteins, peptides, and small molecules with up to 100-fold fluorescence increases and subsecond kinetics, allowing real-time and wash-free target sensing and live-cell bioimaging. An optimized genetic code expansion chemistry with FgAAs further enables rapid (~3 h) ribosomal nanosensor discovery via the cell-free translation of hundreds of candidates in parallel and directed nanosensor evolution with improved variant-specific sensitivities (up to ~250-fold) for SARS-CoV-2 antigens. Altogether, this platform could accelerate the discovery of fluorogenic nanosensors and pave the way to modify proteins with other non-standard functionalities for diverse applications.

Enantioselective Mukaiyama-Michael with 2-enoyl pyridine N-oxides catalyzed by PYBOX-DIPH-Zn(II)-complexes at ambient temperature.

A chiral PYBOX-DIPH-Zn(II) catalyzed enantioselective Mukaiyama-Michael reaction of acyclic silyl enol ethers with 2-enoylpyridine N-oxides has been studied in external additive free conditions at ambient temperature. The methodology offers straightforward access to a variety of functionalized chiral 1,5-dicarbonyl compounds, which could easily be elaborated into synthetically viable pyrones via hydrolysis followed by cyclization. A transition state model has been proposed to explain the stereochemical outcome.

Enantioselective synthesis of 3,4-dihydropyran derivatives via a Michael addition reaction catalysed by chiral pybox-diph-Zn(II) complex.

An enantioselective Michael addition of cyclic 1,3-dicarbonyls to 2-enoylpyridine N-oxides catalyzed by a chiral pybox-diph-Zn(II) complex has been developed. The corresponding Michael adducts have been obtained in high yields with up to >99% ee. The Michael adduct has been transformed to biologically active 2,4-disubstituted hexahydroquinoline. A plausible transition-state model has been proposed to explain the stereochemical outcome of the reaction.

Asymmetric Construction of Remote Vicinal Quaternary and Tertiary Stereocenters via Direct Doubly Vinylogous Michael Addition.

An asymmetric direct doubly vinylogous Michael addition has been developed for the generation of sterically congested vicinal quaternary and tertiary stereocenters. This doubly vinylogous Michael addition of ß,γ-unsaturated butenolides to 3-methyl-4-nitro-5-alkenyl isoxazoles, powered by a bifunctional squaramide, affords a broad range of densely functionalized enantioenriched γ,γ-disubstituted butenolides in high yields with excellent diastereo- and enantioselectivities in most cases. Moreover, the strategy highlights the first application of ß,γ-unsaturated butenolides in an asymmetric 1,6-conjugate addition.

An asymmetric vinylogous Mukaiyama-Michael reaction of α,ß-unsaturated 2-acyl imidazoles catalyzed by chiral Sc(iii)- or Er(iii)-pybox complexes.

A highly diastereo- and enantioselective vinylogous Mukaiyama-Michael reaction of silyloxyfurans with α,ß-unsaturated 2-acyl imidazoles catalyzed by either chiral Sc(iii) or Er(iii) complexes of a pybox ligand has been reported. The enantioenriched γ-butenolides formed in the reaction were further transformed into highly functionalized γ-lactones found as important structural frameworks in a wide range of biologically active natural products.

Asymmetric direct vinylogous Michael addition to 2-enoylpyridine N-oxides catalyzed by bifunctional thio-urea.

Catalytic enantioselective direct vinylogous Michael addition of α,α-dicyanoalkenes to 2-enoylpyridine N-oxides with a bifunctional organocatalyst is described. The methodology offers an efficient way to install an asymmetric carbon-carbon bond at the γ-position of α,α-dicyanoalkenes in excellent regio-, diastereo-, and enantioselectivity. Further, application in desymmetrization of achiral α,α-dicyanoalkene to access highly functionalized enantioenriched cyclohexylidenemalononitrile derivatives has been demonstrated.