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SCPDr Stephen C. Pelly

Title:
Senior Lecturer - Organic and Medicinal Chemistry
Office: 1037 De Beers Building
Phone: +27 (0)21 808-2180
Fax: +27 (0)21 808-3360
E-mail scpelly@sun.ac.za


Educational Background:
PhD, University of the Witwatersrand

Research Emphasis:
Drug Design, Medicinal Chemistry, Organic Synthesis,
Molecular Modelling



analitical chemistry
Analytical Chemistry



chemical chemistry Chemical Biology



inorganic chemistry Inorganic Chemistry


organic chemistry Organic Chemistry


physical chemistry Physical Chemistry



polymer science Polymer Science



supramolecular chemistry & materialsSupra- molecular Chemistry
& Materials
 
 
 

Research Summary:

The field of medicinal chemistry is a particularly rewarding research area as it requires expertise from several diverse backgrounds for a successful research project. Our main research focus is developing anti-HIV compounds, with a specific interest in designing and synthesizing non-nucleoside reverse transcriptase inhibitors and integrase strand transfer inhibitors. To this end we incorporate a significant amount of molecular modelling in the design phases of the project in order to identify novel promising compounds which are synthesized to establish proof of concept. Once this has been accomplished, we embark upon a more extensive synthetic campaign to accumulate SAR data which in turn provides valuable guidance for the ongoing modelling phase of the project, thus leading to optimized compounds in an iterative rational design process. This research is particularly relevant in a South African context, given the enormous social and economic problems we face as a result of a particularly high prevalence of the disease in our country, and indeed, sub-Saharan Africa in general.

This research is made possible by well-equipped laboratories with access to all the required spectroscopic services (in particular, NMR, mass spectrometry and single crystal X-ray diffractometry) as well as modern molecular modeling facilities. Collaborations with groups (both national and international) provides the expertise in areas such as whole cell and enzymatic assays, which are so critical to the overall success of the projects.

 
 
     

Current Projects in HIV Drug Design:

  • Indole Inhibitors
  • Triazole Inhibitors
  • Overcoming Y181C
  • Dual Target Inhibitors
  • The Team

Image1

 

In this, our longest running and most successful project, the indole system has been utilised as an effective scaffold for the design and development of novel, potent, HIV NNRTIs. The initial design emanated from modelling studies, and incorporated a cyclopropyl ring system suitably attached to the indole such that this small hydrophobic functional group occupied the Val179 pocket. This initial concept resulted in the first hit compounds in this series, being moderate inhibitors of HIV right from the start.

 

Image2

 

 

 

The design then evolved to methyl ether derivatives which were highly potent inhibitors of HIV replication for both the wild type strain of the virus, and the problematic K103N resistant strain.  Unfortunately however, these compounds were not stable under acidic conditions. Replacement of the methyl ether with a methyl sulphide solved the acid lability problem, whilst maintaining high efficacy against the virus. Work continues in this project as we determine which enantiomer is the most effective inhibitor, and we suitably functionalise the periphery to enhance efficacy against resistant strains of the virus.

Image3We were inspired by the pyrazole NNRTI Lersivirine, itself originating from the earlier NNRTI Capravirine. LSV is a potent NNRTI which is effective against wild type HIV at low nano-molar concentrations and more importantly, is effective against several problematic mutant strains of the virus, especially the K103N and Y181C mutants where only a marginal decrease in potency is observed. Unfortunately, continued development of LSV was halted recently at the end of phase IIB clinical trials. Nevertheless, the small five membered heterocyclic pyrazole ring serving as a hub for various substituents intrigued us and we were curious as to whether other rings systems could be utilised or this purpose, especially those easily accessible by multi-component coupling reactions. Of particular interest was whether the pyrazole ring could be substituted by a triazole ring, given the versatility in obtaining these systems by way of the Cu(I) catalysed 'click' reaction. In this project, variously substituted triazole systems are bing investigated as potential new and easily accessible HIV NNRTIs.

Image4

Many NNRTIs depend on strong Pi interactions with the aromatic side chain of Tyr181. Although this has proven an effective strategy in the design of inhibitors for wilt type and several mutant variants of the virus, the Y181C mutation usually obliterates the potency of these compounds. In this project, through a careful rational design process, we have purposefully avoided interactions with Tyr181, focussing instead on interactions with Tyr188 and more importantly, the conserved residue, Trp229. This strategy has resulted in the synthesis of several low nanomolar inhibitors, effective against the Y181C resistant strain. Work continues in the project, with the emphasis being on developing inhibitors effective against double mutant variants of the virus.

First line treatment for HIV usually consists of a combination of three drug actives and is referred to as highly active antiretroviral therapy (HAART). Although this polypharmacy approach has proven to be very effective as a front line treatment by providing a higher barrier to the development of resistance and allowing for reduced doses, long term treatment with a cocktail of drugs Image5unfortunately still presents ongoing challenges such as long term toxicity, multidrug resistance and of course, the cost of producing a tablet containing multiple APIs. Of particular interest to current anti-HIV research is that the RNase H site of HIV reverse transcriptase (RT) is very similar to that of the catalytic core domain of HIV integrase (IN). Indeed, both of these enzymes belong to a larger superfamily of polynucleotidyl transferases. This project aims to expand our HIV research program into the area of dual-target inhibitors, with one API pharmacophore capable of targeting both HIV IN and HIV RT at the RNase H pocket. Currently, there are no licensed antiretrovirals which operate via this mechanism, and in fact, the RT RNase H pocket itself is currently not exploited in HIV therapy. Through a rational design approach, we aim to exploit the similarity in these two pockets to design and synthesise potent dual-target antiretrovirals.

group

From left to right:
Moscos Avgenikos, Nicole Pribut, Lana Wessels and Siobhan Brigg.

Selected Publications

  • Novel indole sulfides as potent HIV-1 NNRTIs. Brigg, S.; Pribut, N.; Basson, A. E.; Avgenikos, M.; Venter, R.; Blackie, M. A.; van Otterlo, W. A. L.; Pelly, S. C. Bioorganic & Medicinal Chemistry Letters 2016, 26, 1580-1584.
  • Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities. Medellin, D. C.; Zhou, Q.; Scott, R.; Hill, R. M.; Frail, S. K.; Dasari, R.; Ontiveros, S. J.; Pelly, S. C.; van Otterlo, W. A. L.; Betancourt, T.; Shuster, C. B.; Hamel, E.; Bai, R.; LaBarbera, D. V.; Rogelj, S.; Frolova, L. V.; Kornienko, A. Journal of Medicinal Chemistry 2016, 59, 480-485.
  • Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9-Epipolygodial against Drug-Resistant Cancer Cells. Dasari, R.; De Carvalho, A.; Medellin, D. C.; Middleton, K. N.; Hague, F.; Volmar, M. N. M.; Frolova, L. V.; Rossato, M. F.; De La Chapa, J. J.; Dybdal-Hargreaves, N. F.; Pillai, A.; Mathieu, V.; Rogelj, S.; Gonzales, C. B.; Calixto, J. B.; Evidente, A.; Gautier, M.; Munirathinam, G.; Glass, R.; Burth, P.; Pelly, S. C.; van Otterlo, W. A. L.; Kiss, R.; Kornienko, A. ChemMedChem 2015, 10, 2014-2026.
  • Covalent-Allosteric Kinase Inhibitors. J. Weisner, R. Gontla, L. van der Westhuizen, S. Oeck, J. Ketzer, P. Janning, A. Richters, T. Mühlenberg, Z. Fang, A. Taher, V. Jendrossek, S. C. Pelly, S. Bauer, W. A. L. van Otterlo, D. Rauh, Angewandte Chemie International Edition 2015, 54, 10313-10316
  • Novel indole based NNRTIs with improved potency against wild type and resistant HIV. Muller, R; Mulani, I; Basson, AE; Pribut, N; Hassam, M; Morris, L; van Otterlo, WAL; Pelly, SC. Bioorganic & medicinal chemistry letters 2014, 24, 4371-4380.
  • Synthetic and Biological Studies of Tubulin Targeting C2-Substituted 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins. Scott, R; Karki, M; Reisenauer, MR; Rodrigues, R; Dasari, R; Smith, WR; Pelly, SC; van Otterlo, WAL; Shuster, CB; Rogelj, S; Magedov, IV; Frolova, LV; Kornienko, A. ChemMedChem 2014, 9 1428-1435.
  • Synthesis of 4-Azapodophyllotoxins with Anticancer Activity by Multicomponent Reactions (Review). Botes, MG; Pelly, SC; Blackie, MAL; Kornienko, A; van Otterlo, WAL. Chemistry Of Heterocyclic Compounds 2014, 50, 119-138.
  • C1, C2-ether derivatives of the Amaryllidaceae alkaloid lycorine: Retention of activity of highly lipophilic analogues against cancer cells. Ramesh Dasari, Laetitia Moreno Y. Banuls, Marco Masi, Stephen C. Pelly, Véronique Mathieu, Ivan R. Green, Willem A.L. van Otterlo, Antonio Evidente, Robert Kiss, Alexander Kornienko. Bioorganic & Medicinal Chemistry Letters 2014, 24, 923-927.
  • Novel cyclopropyl-indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors. M. Hassam, A. E. Basson, D. C. Liotta, L. Morris, W. A. L. van Otterlo and S. C. Pelly. ACS Medicinal Chemistry Letters, 2012, 3, 470-475.
  • In search of a treatment for HIV – current therapies and the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs). C. Reynolds, C. B. de Koning, S. C. Pelly, W. A. L. van Otterlo and M. L. Bode. Chemical Society Reviews, 2012, 41, 4657-4670.
  • Bulbispermine: a crinine-type Amaryllidaceae alkaloid exhibiting cytostatic activity toward apoptosis-resistant glioma cells. G. Luchetti, R. Johnston, V. Mathieu, F. Lefranc, K. Hayden, A. Andolfi, D. Lamoral-Theys, M. R. Reisenauer, C. Champion, S. C.  Pelly, W. A. L. van Otterlo, I. Magedov, R. Kiss, A. Evidente, S. Rogelj and A. Kornienko. ChemMedChem, 2012, 7, 815-822.
  • The Antibiotic CJ-15,801 is an antimetabolite that hijacks and then inhibits CoA biosynthesis. R. van der Westhuyzen, J. C. Hammons, J. L. Meier, S. Dahesh, W. J. Moolman, S. C. Pelly, V. Nizet, M. D. Burkart and E. Strauss. Chemistry and Biology, 2012, 19, 559-571.
  • In search of a cytostatic agent derived from the alkaloid lycorine: Synthesis and growth inhibitory properties of lycorine derivatives. N. M. Evdokimov, D. Lamoral-Theys, V. Mathieu, A. Andolfi, L. V. Frolova, S. C. Pelly, W. A van Otterlo, I. V. Magedov, R. Kiss, A. Evidente and A. Kornienko. Bioorganic & Medicinal Chemistry, 2011, 19, 7252-7261.
  • Imidazo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors. M. L. Bode, D. Gravestock, S. S. Moleele, C. W. van der Westhuyzen, S. C. Pelly, P. A. Steenkamp, H. C. Hoppe, T. Khan, L. A. Nkabinde, Bioorganic & Medicinal Chemistry 2011, 19, 4227-4237.
  • Arginine 15 stabilizes an SNAr reaction transition state and the binding of anionic ligands at the active site of human glutathione transferase A1-1. S. Gildenhuys, M. Dobreva, N. Kinsley, Y. Sayed, J. Burke, S. Pelly, G. P. Gordon, M. Sayed, T. Sewell, H. W. Dirr, Biophysical Chemistry 2010, 146, 118-125.
  • Stereoselective syntheses of the 2-isopropenyl-2,3-dihydrobenzofuran nucleus: Potential chiral building blocks for the syntheses of tremetone, hydroxytremetone, and rotenone. S. C. Pelly, S. Govender, M. A. Fernandes, H.-G. Schmalz, C. B. de Koning, The Journal of Organic Chemistry 2007, 72, 2857-2864.
  • Metathesis reactions for the synthesis of ring-fused carbazoles. S. C. Pelly, C. J. Parkinson, W. A. L. van Otterlo, C. B. de Koning, The Journal of Organic Chemistry 2005, 70, 10474-10481.

 

   
 
 
 
 
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