Design, synthesis and biological evaluation of camptothecin analogue FL118 as a payload for antibody-drug conjugates in targeted cancer therapy.

FL118, a camptothecin derivative with dual mechanisms of action through topoisomerase I inhibition and proteasome-mediated degradation of anti-apoptotic proteins exhibits potent anti-tumor activity while remaining resistant to drug efflux transporters. This work describes the targeted delivery of FL118 to tumors via antibody-drug conjugates (ADCs) using the pH-sensitive CL2A linker. ADCs targeting Trop2, HER2, and EGFR exhibited potent in vitro cytotoxicity, with IC values as low as 0.

Integrative Analyses Reveal the Anticancer Mechanisms and Sensitivity Markers of the Next-Generation Hypomethylating Agent NTX-301.

Epigenetic dysregulation characterized by aberrant DNA hypermethylation is a hallmark of cancer, and it can be targeted by hypomethylating agents (HMAs). Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with venetoclax in the treatment of acute myeloid leukemia. Following a previous study, we further explored the therapeutic properties of NTX-301 based on experimental investigations and integrative data analyses.

Late chronotypes are associated with neoadjuvant chemotherapy-induced nausea and vomiting in women with breast cancer.

Neoadjuvant chemotherapy, that is, the administration of chemotherapy before surgery, has been commonly used for locally advanced breast cancer to improve the surgical outcomes and increase the opportunity for breast-conserving therapy. Women with breast cancer often receive an anthracycline-based regimen as the neoadjuvant chemotherapy, which is associated with a high risk of emesis. Despite the development of novel antiemetics, chemotherapy-induced nausea and vomiting (CINV) has been commonly reported as a major adverse effect, affecting the quality of life of the patients.

Phosphoryl azides as versatile new reaction partners in the Cu-catalyzed three-component couplings.

Phosphoryl azide was successfully employed as an efficient reacting partner in the Cu-catalyzed three-component reaction with 1-alkynes and amines to produce the corresponding phosphoryl amidines in high yields. A range of fruitful applicability of the produced amidines was also demonstrated such as an alkoxide exchange and asymmetric alpha-alkylation of optically active BINOL-derived amidines.

Hydrogen-bond-directed highly stereoselective synthesis of Z-enamides via Pd-catalyzed oxidative amidation of conjugated olefins.

An efficient procedure for the preparation of Z-enamides has been developed, involving the reaction of primary amides with conjugated olefins using a Pd/Cu cocatalyst system. It was found that certain additives, such as phosphine oxides and phosphonates, increase the efficiency of the reaction in nonpolar solvents under an oxygen atmosphere, thus producing a variety of Z-enamides in high yields with excellent stereoselectivity under Wacker-type conditions. The oxidative amidation reaction has a broad substrate scope, allowing alkyl, aryl, and vinyl amides to react with olefins conjugated with ester, amide, phosphonate, and ketone groups.

Catalytic one-pot synthesis of cyclic amidines by virtue of tandem reactions involving intramolecular hydroamination under mild conditions.

A new synthetic methodology for the generation of cyclic amidines has been developed by the reaction of 1,n-aminoalkynes with electron-deficient azides using a ruthenium catalyst at ambient temperature. The reaction proceeds most likely via a tandem sequence of intramolecular hydroamination of aminoalkynes, cycloaddition of azides with the resulting enamines, and rearrangement of triazoline intermediates. It demonstrates, as the proof-of-principle, that an equilibria cascade sequence can be favorably driven by an irreversible step, thus enabling a facile one-pot synthetic route to deliver molecular complexity under unprecedented mild conditions without relying on the traditional linear approaches.