Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach.

Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chemical probes consisting of a focused-chemical-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chemical reactions carefully chosen from a list of one-step organic transformations relevant in medicinal chemistry. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compounds with improved affinity by several orders of magnitude.

Total synthesis of indole-derived allocolchicine analogues exhibiting strong apoptosis-inducing activity.

A series of novel pyrrolo-allocolchicine derivatives (containing a 1-methyl-1H-indol-5-yl moiety replacing ring C) was synthesized. The tetracyclic ring system was constructed by Suzuki-Miyaura cross-coupling of a 1-methylindole-5-boronate with an ortho-iodo-dihydrocinnamic acid derivative and subsequent intramolecular Friedel-Crafts acylation. After reduction of the resulting ketone, the nitrogen functionality was introduced in a Mitsunobu-type reaction by using zinc azide followed by LiAlH(4) reduction. Structural assignments were supported by X-ray crystallography. The compounds synthesized were then tested against BJAB tumor cells and found to exhibit pronounced cytotoxic activity (proliferation inhibition and apoptosis induction). The ketone 24 b was even active at sub-nanomolar concentration. In addition, the antitumor potential of the compounds was confirmed by using B lymphoid cell lines.