Abstract
A total of 42 trisubstituted carboranes categorised into five scaffolds were systematically designed and synthesized by exploiting the different reactivities of the twelve vertices of o-, m-, and p-carboranes to cover all directions in chemical space. Significant inhibitors of hypoxia inducible factor transcriptional activitay were mainly observed among scaffold V compounds (e.g., Vi–m, and Vo), whereas anti-rabies virus activity was observed among scaffold V (Va–h), scaffold II (IIb–g), and scaffold IV (IVb) compounds. The pharmacophore model predicted from compounds with scaffold V, which exhibited significant anti-rabies virus activity, agreed well with compounds IIb–g with scaffold II and compound IVb with scaffold IV. Normalized principal moment of inertia analysis indicated that carboranes with scaffolds I–V cover all regions in the chemical space. Furthermore, the first compounds shown to stimulate the proliferation of the rabies virus were found among scaffold V carboranes.
Highlights
Of trisubstituted carboranes can be designed that satisfy all directions in a chemical space, as can be evinced from Fig. 1a
We developed tricyclic three-dimensional scaffolds that are rich in sp3-hybridized carbon centres to access unexplored chemical spaces, and we used these scaffolds to design peptidomimetic molecules[33,34,35]
The α-helix is one of the important elements of a protein’s secondary structure that affords the construction of three-dimensional tertiary structures of proteins. It is a structure found in many protein–protein interactions (PPIs)[36], and the α-helix plays an important role in biological networks[37,38,39]
Summary
Of trisubstituted carboranes can be designed that satisfy all directions in a chemical space, as can be evinced from Fig. 1a. The TBS group was removed, and the resulting alcohol was esterified with isovaleryl chloride to afford compound 6 in 90% yields over two steps.
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