2 research outputs found

    2‑Aminopyridines via Reaction of Pyridine <i>N</i>‑Oxides and Activated Isocyanides

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    A practical and efficient method for the synthesis of substituted 2-aminopyridines from pyridine <i>N</i>-oxides is reported. Yields of purified, isolated products of up to 84% are observed for the one-pot, two-step process. The reaction involves an in situ deprotection of an isolable <i>N</i>-formylaminopyridine intermediate and facilitates the synthesis of 2-aminopyridines for which other methods fail

    Expedient Synthesis of Highly Potent Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Unique Selectivity for ML-IAP

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    A series of novel, potent antagonists of the inhibitor of apoptosis proteins (IAPs) were synthesized in a highly convergent and rapid fashion (≤6 steps) using the Ugi four-component reaction as the key step, thus enabling rapid optimization of binding potency. These IAP antagonists compete with caspases 3, 7, and 9 for inhibition by X chromosome-linked IAP (XIAP) and bind strongly (nanomolar binding constants) to several crucial members of the IAP family of cancer pro-survival proteins to promote apoptosis, with a particularly unique selectivity for melanoma IAP (ML-IAP). Experiments in cell culture revealed powerful cancer cell growth inhibitory activity in multiple (breast, ovarian, and prostate) cell lines with single agent toxicity at low nanomolar levels against SKOV-3 human ovarian carcinoma cells. Administration of the compounds to human foreskin fibroblast cells revealed no general toxicity to normal cells. Furthermore, computational modeling was performed, revealing key contacts between the IAP proteins and antagonists, suggesting a structural basis for the observed potency
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