Organic synthesis toward small-molecule probes and drugs

Abstract

"Organic synthesis" is a compound-creating activity often focused on biologically active small molecules. This special issue of PNAS explores innovations and trends in the field that are enabling the synthesis of new types of small-molecule probes and drugs. This perspective article frames the research described in the special issue but also explores how these modern capabilities can both foster a new and more extensive view of basic research in the academy and promote the linkage of life-science research to the discovery of novel types of small-molecule therapeutics [Schreiber SL (2009) Chem Bio Chem 10:26-29]. This new view of basic research aims to bridge the chasm between basic scientific discoveries in life sciences and new drugs that treat the root cause of human disease--recently referred to as the "valley of death" for drug discovery. This perspective article describes new roles that modern organic chemistry will need to play in overcoming this challenge.

Fig. 1.

Advances in diastereoselective catalysis facilitated the discovery of eribulin. Variations on Nozaki–Hiyama–Kishi reactions using chiral catalysts resulted in unprecedented control of stereochemistry during key convergent couplings involving the formation of carbon/carbon bonds. These coupling reactions were central to an efficient synthesis of eribulin, a novel drug recently approved for the treatment of advanced breast cancer.

Fig. 2.

Build/couple/pair strategy of diversity synthesis yielding, following optimization studies of an initial “hit” in a live/dead malarial parasite screen, a promising malaria drug candidate having a novel mechanism of action. This strategy in organic synthesis can yield candidate probes or drugs having structural features that correlate with highly selective binding, including to proteins lacking enzymatic activity. It can also yield compounds well suited for optimization (“follow-up chemistry” for probes and “medicinal chemistry” for drugs). In this example, chemists synthesized or purchased building blocks (only two of many shown) having “orthogonal” functionality that permitted intermolecular coupling followed by intramolecular pairing of indole and imine functionality. Novel spirocyclic products of the indicated Pictet–Spengler reaction yielded a starting point for a drug discovery effort in malaria. The ease of optimization of the starting point facilitated the discovery of an extraordinary compound that eliminates the malaria parasite in an animal model by a novel mechanism of action (27).

Fig. 3.

Proposal for bridging the valley of death. (Upper) Current academic research yields concepts potentially related to human health, but their relevance to human clinical outcomes is difficult to assess—thereby contributing to the valley of death (31). (Lower) Building on and expanding recent models of academic research [for example, the National Institutes of Health-sponsored Molecular Libraries Probe Centers Network (MLPCN) and Centers of Excellence in Chemical Methodology and Library Design (CMLD)] provide a solution, where basic research spans new concepts in human disease that are tested using small molecules in physiologically relevant settings. Here, it is anticipated that small-molecule probes (or drugs) with mechanisms of action that are rigorously established are used in disease models to test hypotheses. Positive outcomes provide much greater confidence in the merits of a full drug discovery and development program by, for example, the pharmaceutical industry. In some instances, for example in rare and neglected diseases or ones requiring new approaches to clinical research, academic efforts might also entail the development of the clinical candidate.