H. Lee Moffitt Cancer Center & Research Institute

Faculty Rank:

Associate Member

USF Affiliations/College Department:

• Arts & Sciences / Chemistry
• Medicine / Oncologic Sciences

Research Interests:

Dr. Lawrence's group efforts are focused on the synthesis of new anticancer agents. The goal of the laboratory is to design and develop synthetic methodology to provide small organic molecules to act as selective anticancer agents against a range of molecular targets.

Our research concerns the development of new anticancer drugs using a combination of synthetic chemistry and natural product isolation; it involves a very productive collaborative program incorporating both chemistry and biology. One aspect of our research concerns the design and function of tumor vasculature targeting anticancer agents that interact with the elements of the cytoskeleton. We are investigating the nature of the colchicine-binding site of Beta-tubulin by the design of appropriate photo-affinity labeling agents and molecular modeling methods. Our laboratory is developing new anticancer agents based on agents related to combretastatins. These agents show potent activity in vitro and in vivo and are currently being prepared via serial and parallel synthesis for evaluation as tumor vasculature targeting drugs. The program also involves the structure activity study of complex derivatives of cucurbaticins. Natural products feature highly in our research, particularly as lead structures in the drug development process. The discovery of new bioactive natural products can often be a laborious venture. We are therefore developing novel natural product isolation techniques to help identify new structures with anticancer activity.

Our research also concerns the development of novel synthetic methodology. This has included methods for the clean asymmetric reduction of ketones using polymeric siloxanes. We are now developing new reagents for use in design and preparation of combinatorial libraries. Our a long-standing interest in multi-component reactions based on vicarious nucleophilic aromatic substitution now provides new processes for the rapid construction of molecular scaffolds for the development of combinatorial libraries for use in the high throughput screening lab.

Key words: Drug discovery, organic synthesis, bioorganic and medicinal chemistry, combinatorial chemistry, natural products, peptidomimetics.

Publications:

1. Ducki S, Mackenzie G, Greedy B, Armitage S, Chabert JF, Bennett E, Nettles J, Snyder JP, Lawrence NJ. Combretastatin-like chalcones as inhibitors of microtubule polymerisation. Part 2: Structure-based discovery of alpha-aryl chalcones. Bioorg Med Chem. 2009 Nov;17(22):7711-7722. Pubmedid: 19837594.   Pubmed ID: 19837594

2. Ducki S, Rennison D, Woo M, Kendall A, Chabert JF, McGown AT, Lawrence NJ. Combretastatin-like chalcones as inhibitors of microtubule polymerization. Part 1: synthesis and biological evaluation of antivascular activity. Bioorg Med Chem. 2009 Nov;17(22):7698-7710. Pubmedid: 19837593.   Pubmed ID: 19837593

3. Lawrence HR, Li Z, Yip ML, Sung SS, Lawrence NJ, McLaughlin ML, McManus GJ, Zaworotko MJ, Sebti SM, Chen J, Guida WC. Identification of a disruptor of the MDM2-p53 protein-protein interaction facilitated by high-throughput in silico docking. Bioorg Med Chem Lett. 2009 Jul;19(14):3756-3759. Pubmedid: 19457663.   Pubmed ID: 19457663

4. Wei J, Kitada S, Rega MF, Emdadi A, Yuan H, Cellitti J, Stebbins JL, Zhai D, Sun J, Yang L, Dahl R, Zhang Z, Wu B, Wang S, Reed TA, Wang HG, Lawrence N, Sebti S, Reed JC, Pellecchia M. Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins. Mol Cancer Ther. 2009 Apr;8(4):904-913. Pubmedid: 19372563.   Pubmed ID: 19372563

5. Wei S, Chen X, Rocha K, Epling-Burnette PK, Djeu JY, Liu Q, Byrd J, Sokol L, Lawrence N, Pireddu R, Dewald G, Williams A, Maciejewski J, List A. A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci U S A. 2009 Aug;106(31):12974-12979. Pubmedid: 19470455.   Pubmed ID: 19470455

6. Kinkade R, Dasgupta P, Carie A, Pernazza D, Carless M, Pillai S, Lawrence N, Sebti S, Chellappan S. A small molecule disruptor of Rb/Raf-1 interaction inhibits cell proliferation, angiogenesis, and growth of human tumor xenografts in nude mice. Cancer Res. 2008 May;68(10):3810-3818. Pubmedid: 18483265.   Pubmed ID: 18483265

7. Lawrence HR, Pireddu R, Chen L, Luo Y, Sung SS, Szymanski AM, Yip ML, Guida WC, Sebti SM, Wu J, Lawrence NJ. Inhibitors of Src homology-2 domain containing protein tyrosine phosphatase-2 (Shp2) based on oxindole scaffolds. J Med Chem. 2008 Aug;51(16):4948-4956. Pubmedid: 18680359.   Pubmed ID: 18680359

8. Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, Sebti SM, Turkson J. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A. 2007 May;104(18):7391-7396. Pubmedid: 17463090.   Pubmed ID: 17463090

9. Chen L, Sung SS, Yip ML, Lawrence HR, Ren Y, Guida WC, Sebti SM, Lawrence NJ, Wu J. Discovery of a novel shp2 protein tyrosine phosphatase inhibitor. Mol Pharmacol. 2006 Aug;70(2):562-570. Pubmedid: 16717135.   Pubmed ID: 16717135

10. Lawrence N, Patterson R, Ooi L, Cook D, Ducki S. Effects of alpha-substitutions on structure and biological activity of anticancer chalcones. Bioorg Med Chem Lett. 2006 Nov;16(22):5844-5848. Pubmedid: 16949281.   Pubmed ID: 16949281

11. Ducki S, Mackenzie G, Lawrence N, Snyder JP. Quantitative structure-activity relationship (5D-QSAR) study of combretastatin-like analogues as inhibitors of tubulin assembly. J Med Chem. 2005 Jan;48(2):457-465. Pubmedid: 15658859.   Pubmed ID: 15658859

12. Guo F, Rocha K, Bali P, Pranpat M, Fiskus W, Boyapalle S, Kumaraswamy S, Balasis M, Greedy B, Armitage E, Lawrence N, Bhalla K. Abrogation of heat shock protein 70 induction as a strategy to increase antileukemia activity of heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin. Cancer Res. 2005 Nov;65(22):10536-10544. Pubmedid: 16288046.   Pubmed ID: 16288046

13. Hadfield J, Gaukroger K, Hirst N, Weston A, Lawrence N, McGown A. Synthesis and evaluation of double bond substituted combretastatins. Eur J Med Chem. 2005 Jun;40(6):529-541. Pubmedid: 15922837.   Pubmed ID: 15922837

14. Lawrence N, McGown A. The chemistry and biology of antimitotic chalcones and related enone systems. Curr Pharm Des. 2005;11(13):1679-1693. Pubmedid: 15892668.   Pubmed ID: 15892668

15. Lawrence NJ, Davies CA, Gray M. Synthesis of diaryl acetates and oxindoles via a sequential VNS(Ar)-S(N)Ar three-component coupling reaction. Org Lett. 2004;6:4957-4960. Pubmedid: 15606109.   Pubmed ID: 15606109

16. Gaukroger K, Hadfield J, Lawrence N, Nolan S, McGown A. Structural requirements for the interaction of combretastatins with tubulin: how important is the trimethoxy unit. Org Biomol Chem. 2003;1(17):3033-3037. Pubmedid: 14518125.   Pubmed ID: 14518125

17. Lawrence N, Rennison D, McGown A, Hadfield J. The total synthesis of an aurone isolated from Uvaria hamiltonii: aurones and flavones as anticancer agents. Bioorg Med Chem Lett. 2003;13(21):3759-3763. Pubmedid: 14552774.   Pubmed ID: 14552774

18. Lawrence N, Liddle J, Bushell S, Jackson D. A three-component coupling process based on vicarious nucleophilic substitution (VNS(AR))-alkylation reactions: an approach to indoprofen and derivatives. J Org Chem. 2002;67(2):457-464. Pubmedid: 11798318.   Pubmed ID: 11798318

19. Gaukroger K, Hadfield J, Hepworth L, Lawrence N, McGown A. Novel syntheses of cis and trans isomers of combretastatin A-4. J Org Chem. 2001;66(24):8135-8138. Pubmedid: 11722216.   Pubmed ID: 11722216

20. Lawrence N, McGown A, Nduka J, Hadfield J, Pritchard R. Cytotoxic Michael-type amine adducts of alpha-methylene lactones alantolactone and isoalantolactone. Bioorg Med Chem Lett. 2001;11(3):429-431. Pubmedid: 11212128.   Pubmed ID: 11212128

21. Lawrence N, Rennison D, McGown A, Ducki S, Gul L, Hadfield J, Khan N. Linked parallel synthesis and MTT bioassay screening of substituted chalcones. J Comb Chem. 2001;3(5):421-426. Pubmedid: 11549359.   Pubmed ID: 11549359

22. Lawrence N, Rennison D, Woo M, McGown A, Hadfield J. Antimitotic and cell growth inhibitory properties of combretastatin A-4-like ethers. Bioorg Med Chem Lett. 2001;11(1):51-54. Pubmedid: 11140732.   Pubmed ID: 11140732

23. Lawrence N, McGown A, Ducki S, Hadfield J. The interaction of chalcones with tubulin. Anticancer Drug Des. 2000;15(2):135-141. Pubmedid: 10901301.   Pubmed ID: 10901301