Medicinal Chemistry



Multicomponent Reactions for a fast Entry to Libraries of Aza-podophyllotoxins: Identifying unique anti-Leukemic Agents


Goal: Development of multicomponent reactions (3CR and 4CR) for the synthesis of aza-podophyllotoxin heterocycles. Libraries of compounds are mostly prepared by undergraduate students (over 90% of compounds synthesized) and tested against various cancer and healthy cell lines for SAR studies. Student: NagaLakshmi Jeedimalla

UG Students: Madison Flint, Aleem Khan, Rhonda Penn

Collaborator: Dr. Alberto Haces (FAU), Prof. James Inglese (NIH; NCATS), Dr. Dmitriy Minond (Torrey Pines) and Eli Lilly for biological testing

Funding: Elsa U. Pardee Foundation (planned submission for spring 2015, Dr. Minond as Co-PI).


Background. The heterolignan podophyllotoxin (1) is known to inhibit the assembly of tubulin into microtubules through tubulin binding, but its high toxicity has limited application as a drug compare to its glycon-analog etoposide which is currently used in cancer chemotherapy. The 4-aza-structural analogues 2 have also shown important biological activity as insecticides, tubulin inhibitors and vascular-disrupting agents (Fig. 1). While numerous aza-podophyllotoxins have been identified as lead molecules in several chemical biology programs (Servier, NCI-60), our synthetic abilities to diversify the current portfolio of these heterocycles is limited. Mechanistic investigations are pursued in our laboratory to determine a plausible mechanism of the multicomponent reaction involving tetronic acid with aldehydes and anilines to design an improved synthesis of aza-podophyllotoxins.

Objectives: 4-Aza-2,3-dePicture5hydropodophyllotoxins 2 were previously prepared using a three component reaction developed by Husson in the early 90’s (Husson-3CR) between variously substituted anilines 3, aldehydes 4 and tetronic acid 5 (Figure 1). Starting a new medicinal chemistry program, we decided to revisit the synthesis to prepare new structural variations of this chemotype. Our mechanistic inquiries lead rapidly to an improved synthetic protocol highlighting the beneficial addition of an electronically poor aniline component. Using the “sacrificial aniline” strategy, a series of 50 novel aza-podophyllotoxins 2 were synthesized in much higher yields (up to threefold) relative to the typical Husson-3CR (Fig. 2). We now propose a second generation of synthesis directed towards a novel 4CR and an asymmetric synthesis of 4-aza-podophyllotoxin derivatives to expand the current library of analogues to chiral molecules. This study is undertaken by an undergraduate in the group: Aleem Khan, to assess if α-amino acids can used to replace ammonium acetate in the reaction to possibly achieve a highly stereoselective 4CR.


The biological evaluation of the library was effected partially by Eli Lilly and recently fully exploit by our collaborator Dr. Minond. During the biological screening, 2 structures have been identified with low picomolar activity as lead compounds for further development (IC50 ~ pM against Leukemia cells All and IC50 > 10 nM against healthy cells).

Publications. 1) Jeedimalla, N.; Johns, J.; Roche*, S. P. Tetrahedron Lett. 2013, 54, 5845–5848. “Mechanistic Investigation and Implications of a Sacrificial Aniline for the Tandem Cascade Synthesis of 4-Aza-podophyllotoxin Analogues.”

2) Flint, M.; Jeedimalla, N.; Haces, A.; Minond*, D.; Roche*, S. P. (submitted to J. Med. Chem. Lett. 2015) A multicomponent strategy for the rapid generation of a medium-sized library of Aza-podophyllotoxin analogues: Discovery of two highly selective and potent anti-leukemic agents.






Light Switch Orchestration of a Tandem visible-light Photocatalysis


Goal: Discovery of a tandem chemical reaction mediated by a simple visible-light wavelength switch. Two visible light photocatalysts functioning in a tandem catalysis are studied for the synthesis of THPP heterocycles. Students: Krishna Yadavalli

UG Students: Benjamin Manga, Nathalie Ramos

Collaborator: Prof. Ken Dawson-Scully (FAU)

Funding: NIH R15/R21 (planned submission for spring 2015, Prof. K. Dawson-Scully Co-PI)


Background. In the last ten years, there have been large investments in providing academic institutions with the best technical and intellectual capabilities for early-stage drug discovery programs, and yet what are the outcomes of this venture? While many High-Throughput Screening (HTS) facilities, medicinal chemistry, chemical biology and small-molecule drug discovery centers blossomed in the most performing Universities around the U.S.A., the impact of the investment in academic drug discovery (ADD) remains limited. Academia and Pharma share a similar approach for early-stage drug discovery, depending on a relatively slow and expensive mechanism (about 10 years of investigation) before reaching the critical bottle neck of the process: the clinical trials phases in which most lead molecules are abandoned (Figure 1). Indeed there is an important need in designing a new paradigm for ADD that will allow all research capabilities to progress simultaneously and in synergy to accelerate the traditional mechanism for discovery while maintaining innovation towards better medicine. Our project is to synthesize expediently some medium-sized libraries of small-molecules by crafting known FDA approved drugs to demonstrate the new paradigm for accelerated drug discovery.


Fig. 1. Integrating Chemistry and Biology: a New Paradigm for Drug Discovery

Objectives. Our objective is to validate a new paradigm for faster ADD programs in which the early-stage process for lead compounds discovery and efficacy optimization for clinical trials will be achieved over a 2 to 3 year period. To this aim, an interdisciplinary synergistic effort is required, Roche will achieve both syntheses of complex therapeutic agents (natural products) and libraries of bioactive small-molecules, while Dawson-Scully will demonstrate how behavioral assays on Drosophila may revolutionize our current approach to biological evaluation. Having an appropriate physiological model of a targeted human disease modeled and validated in vivo on Drosophila behavior and physiology, will not only serve as a fast-throughput screening tool for medium-sized libraries of small-molecules, but also enable simultaneous biological feedback for chemical optimization. For the two targeted diseases (stroke and type-II diabetes), we will assemble two medium-sized libraries of small-molecules using a fragment-based approach mimicking two pre-identified biological-target substrates: a) dipeptidyl peptidase-4 (DPP4) inhibitors, (sitagliptin® analogues) and b) protein kinase G (PKG) pathway activators (analogues of cyclic guanosine monophosphate (cGMP), sildenafil®).

Chemistry. We will prepare the first-generation library of tetrahydropyrrolo[1,2-a]pyrazine (THPP) scaffolds (7 compounds) for the synthesis of a medium-sized library of sitagliptin analogues (+42 compounds), as well as several sildenafil analogues through late stage functionalization. Discovery phase 1 requires a small set of molecules for screening on the genetically-modified fly models. For this purpose, a novel chemical method is being developed to assemble the THPP scaffolds highlighted by a unique and unprecedented visible-light photocatalysis tandem process which will be mediated by a simple wavelength switch.


Future. We expect to validate a proof of principle for a novel and synergistic approach to ADD, which rapidly generates viable drug candidates for clinical trials. This concept will likely be expanded to other disease models in Drosophila, which would enable us and others to test numerous and more sophisticated compound libraries, identify new biological probes to study fundamental biological targets and mechanisms, and potentially discover more specific therapeutic agents for a better medicine.


Publications. Manga, B.; Yadavalli, K.; Mavlan, M.; Roche, S. P. (preparation for Tetrahedron Lett. 2015-2016) Perfluoroalkylation of arenes mediated by visible-light photocatalysis.

Leave a Reply

Your email address will not be published. Required fields are marked *