In one go: (Hetero)aryl iodides, alkynes, carbon monoxide, and amidines can be assembled in a consecutive four‐component reaction to give pyrimidines by a sequence of carbonylative alkynylation and cyclocondensation. Carbonylative alkynylation also is the key step in the two‐step syntheses of meridianins and meridianin derivatives.

Mild conditions! Decarbonylative carbonylation by consecutive glyoxylation of indoles, 7-aza-indoles, or pyrroles with oxalyl chloride and subsequent Pd/Cu-catalyzed decarbonylative alkynylation with terminal alkynes furnishes alkynones under very mild conditions. 4-(Indol-3-yl)-, 4-(7-aza-indol-3-yl)-, and 4-(pyrrol-2-yl)-2-amino pyrimidines can be readily obtained in a concise two-step synthesis starting from N-substituted indoles, 7-aza-indoles, or pyrroles (see scheme).

Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamine platinum(II) moiety, herein called Lx, was coordinated to Desferal (DFO) or auristatin F (AF) to provide storable "semifinal" products, which were directly conjugated to unmodified mAbs. Conjugation resulted in ADCs with unimpaired mAb-binding characteristics, DAR in the range of 2.5 to 2.7 and approximately 85% payload bound to the Fc region, presumably to histidine residues. To evaluate the in vivo stability of Lx and its effect on pharmacokinetics and tumor targeting of an ADC, Lx-DFO was conjugated to the HER2 mAb trastuzumab, followed by radiolabeling with Zr. Trastuzumab-Lx-DFO-Zr was stable in vivo and exhibited pharmacokinetic and tumor-targeting properties similar to parental trastuzumab. In a xenograft mouse model of gastric cancer (NCI-N87) or an ado-trastuzumab emtansine-resistant breast cancer (JIMT-1), a single dose of trastuzumab-Lx-AF outperformed its maleimide benchmark trastuzumab-Mal-AF and FDA-approved ado-trastuzumab emtansine. Overall, our findings show the potential of the Lx technology as a robust conjugation platform for the preparation of anticancer ADCs. Cancer Res; 77(2); 257-67. ©2016 AACR.

One step back, two steps forward! Starting from diverse heterocycles, the title reaction furnishes ynediones under very mild conditions in a direct and preparatively simple one‐pot process. The key to avoiding decarbonylation is the CuI‐catalyzed Stephens–Castro alkynylation rather than the usually more efficient Sonogashira coupling. In addition, novel highly atom‐economical four‐component syntheses of various heterocycles can be achieved.

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