Chemists Design Novel One-Pot Reactions to Access Complex Natural Product Analogs for Drug Discovery

Scientists, led by Prof. Taleb H. Al-Tel, at the University of Sharjah in the United Arab Emirates have discovered powerful new reactions for the diastereo- and enantio-selective synthesis of nature-inspired privileged structures – one-pot, modular, elegantly designed chemical reactions that could minimize the gap between the chemical and biological space. Their contribution, detailed in the journal Nature Communications, 26th of November 2018; DOI: 10.1038/s41467-018-07521-2, could be a turning point for the discovery of unmet diseases.

The Nature Communications article describes a one-step chemo-, diastereo- and enantio-selective protocol for the construction of densely functionalized octahydroindolo[2,3-a]quinolizine systems with three to five contiguous chiral centers. This protocol employs tandem cycloaddition processes utilizing Pictet-Spengler/aza-Michael addition, the products of which constitute the basic framework of the biologically significant natural products yohimbine, venenatine, alstovenine and tangutorine. Phenotypic screening of the library identified chemical probes that effectively block ATP synthesis, mitochondrial membrane potential (ΔΨm), elevate the level of reactive oxygen species (ROS) and suppress cellular proliferation without altering the immunological activation or the metabolic reprogramming of T- and B-cells, representing a promising approach for cancer immunotherapy.

Natural products and their analogs

Natural products are produced by living organisms and encompass a fascinating range of structural diversity and potentially useful biological activities. In fact, over 50% of the drugs approved by the FDA during the past 25 years are derived from or inspired by natural products. Some of these well-known natural products include a octahydroindolo[2,3-a]quinolizine ring system that forms the basic framework of a monoterpene family, comprised of more than 2000 distinct members, that display interesting and contrasting biological activities. Recent advances in genomics/proteomics/transcriptomics and molecular biology have guided the discovery of novel biological activities of natural products or their analogs. However, the limited quantities of natural materials and the environmental concerns associated with harvesting the producing species highlight the importance of using alternate methods to synthesize these biologically active compounds. Thus, through a synthesis approach, organic chemists are able to provide a renewable source of the natural product and analogs thereof to generate a collection of nature-inspired compound collections for extensive phenotypic screening.

The focus of Professor Al-Tel's Research Program is the synthesis of nature-inspired compounds that represent potential lead drug candidates for the treatment of human diseases. In particular, his group focuses on developing novel synthetic pathways to manufacture sufficient quantities of natural product analogs that hold potential for the treatment of cancer, diabetes, infectious diseases and immunological disorders. The team’s work involves the development of innovative one-pot synthetic reactions that will allow them to construct complex natural product-like compounds in a cascade manner from simple chemical building blocks. The synthesis of these molecules will also enable the discovery of new substances that are similar in structure to these natural products but with potentially improved pharmaceutical properties. Moreover, key opportunities in expanding chemical space are presented, including the increasingly important syntheses that introduce high three-dimensional molecular shapes.

Collaboration is key

Prof. Taleb H. Al-Tel, a synthetic medicinal chemist and expert in chemical synthesis, joined research teams at the Sharjah Institute of Medical Research, to create new carbon-carbon, carbon-heteroatom bond reactions that are fundamental for the discovery of small-molecule lead drug candidates. The reactions utilize a three-directional strategy using a pluripotent building block for the de novo design of complex and skeletally diverse nature-inspired frameworks. The novel chemistry, employs metal, e.g. Sc(OTf)₃ and non-metal catalysts, to sew atoms together into complex, molecular rings with high 3D-cotents and more than three contagious chiral centers. The new reactions, created in Al-Tel's lab, combine more than one reaction in a cascade fashion. Al-Tel's creation thus allows for easy construction of traditionally difficult-to-make chemical compounds that are known biological targets. They offer potential for discovery of drugs for diseases old and new – a new arsenal of tools previously out of reach.

"A major goal for our lab has always been for anyone in a research or industry setting to try out our new chemistry," explains Al-Tel. "If people can pick this up and start to use it to discover new drug leads, that would be an incredible achievement. In the past 3 years, we have developed many novel chemical reactions, to get such a novel approach in there hasn’t been easy, but we consider it a remarkable achievement.”

“Collaborating with Prof. Saleh Ibrahim’s lab at Luebeck University, was integral to the discovery of important biological activities of our designed compound collections – because chemical experimentation alone could not have yielded their resulting model,” says Al-Tel.

“In another aspect, collaboration with Prof. Scott Sieburth’s lab at Temple University was crucial to the success of our story. Sieburth’s lab specializes in higher order cycloaddition reactions, using to rational design of new chemical structures to carry out specific tasks,” explains Al-Tel.

“Without these collaborations, the biology, the mechanisms and stereochemistry by which the challenging molecular architectures are orchestrated, would not have been possible.”

What does this mean for drug discovery?

Al-Tel highlights the significance of their findings: "This is the first study we know of its kind that provides a complete understanding of how these molecules are made in one step, and how they possess such important biological activities. Before, researchers had viewed these structures as somewhat mysterious and difficult to make in one-step.” 

The strategies being developed have enabled another three novel reactions for the synthesis of oxocanes, spiro-oxoindolo-carbolines and piperazinones, that will be valuable to drug discovery campaigns. The researchers hope that medicinal chemists will utilize this new chemistry to access compound libraries, that could open the doors for the discovery of new treatments.

“We want to donate these novel one-pot synthetic methods to researchers to enable them to make important and smart chemical navigators.”

Author:        Taleb H. Al-Tel^1,2
Affiliation:    (1) Sharjah Institute for Medical Research, University of Sharjah, P.O. Box 27272, Sharjah, UAE    
                  (2) College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, UAE