The alpha(V)beta(3) integrin receptor plays an important role in human tumor metastasis and tumor-induced angiogenesis. The in vivo inhibition of this receptor by antibodies or by cyclic peptides containing the RGD sequence may in the future be used to selectively suppress these diseases. Here we investigate the influence of N-methylation of the active and selective alpha(V)beta(3) antagonist cyclo(RGDfV) (L1) on biological activity. Cyclo(RGDf-N(Me)V-) (P5) was found to be even more active than L1 and is one of the most active and selective compounds in inhibiting vitronectin binding to the alpha(V)beta(3) integrin. Its high-resolution, three-dimensional structure in water was determined by NMR techniques, distance geometry calculations, and molecular dynamics calculations, providing more insight into the structure-activity relationship.
The efficient preparation of heterocycles with a range of substitutions ortho to heteroatoms remains as a challenge in organic synthesis, particularly relevant to the construction of druglike molecules due to the ubiquitous presence of such moieties in that chemical space. Modular installation of heterocyclic building blocks using Suzuki-Miyaura cross-coupling is a conceptually useful strategy to address this challenge, though this has historically been met with technical difficulty due to issues of inaccessibility and instability of the requisite heterocyclic boronates. Herein we report a mild and highly regioselective cycloaddition approach which affords convenient access to stable MIDA boronate-functionalized isoxazoles and triazoles and their subsequent efficient Suzuki-Miyaura cross-coupling. This methodology is then further applied to a set of druglike compounds in an efficient one-pot telescoped sequence in line with green chemistry principles.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.