Molecular Target Focused Discovery of Anticancer Drugs

Summary

Principal Investigator: GEORGE PETTIT
Abstract: The very vigorous and sharply focused objective of the continuation research will be the accelerated discovery and preclinical development of new and structurally unique anticancer drug candidates for the U.S. National Cancer institute. Emphasis will continue to be devoted to small molecule anticancer constituents isolated from terrestrial arthropods, marine organisms, microorganisms and plants followed by structural determinations, syntheses and/or structural modifications. Special emphasis will be placed on new antineoplastic substances either isolated based on molecular target bioassays or subsequently displaying such potent antiangiogenesis, cancer vascular targeting, tubulin and/or various cancer-implicated kinase (cyclin-dependent, protein kinase C, tyrosine kinase and telomerase) properties as well as exceptionally strong antineoplastic activity. Additional emphasis will be placed on further research necessary to advancing the expanding clinical trials of the auristatins, bryostatin 1, the dolastatins, and others we discovered such as the powerful cancer antiangiogenesis and vascular targeting drugs in the combretastin (CA4P, CA1P) and other series. Only those leads from confirmed active extracts of arthropods, marine invertebrates, marine and terrestrial plants, and marine as well as terrestrial microorganisms that give maximum promise of yielding new drugs with potential clinical activity will be pursued. The proposed continuation research will provide great assistance to the DCTD/NCI in selecting new anticancer drugs candidates and speeding their development toward clinical trials. In summary, the proposed research will be sharply aimed at the discovery and very rapid development of new anticancer drugs for the NCI programs direct at improving human cancer treatments.
Funding Period: 2001-04-01 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Stylopeptide 2, a proline-rich cyclodecapeptide from the sponge Stylotella sp
    Mary R Brennan
    Gustaf H Carlson School of Chemsitry and Biochemistry, Clark University, Worcester, Massachusetts 01610, USA
    J Nat Prod 71:453-6. 2008
  2. pmc Antineoplastic agents. 595. Structural modifications of betulin and the X-ray crystal structure of an unusual betulin amine dimer
    George R Pettit
    Department of Chemistry and Biochemistry, Arizona State University, P O Box 871604, Tempe, Arizona 85287 1604, United States
    J Nat Prod 77:863-72. 2014
  3. pmc Isolation and structures of axistatins 1-3 from the Republic of Palau marine sponge Agelas axifera Hentschel
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P O Box 871604, Tempe, Arizona 85287 1604, USA
    J Nat Prod 76:420-4. 2013
  4. pmc Antineoplastic agents. 579. Synthesis and cancer cell growth evaluation of E-stilstatin 3: a resveratrol structural modification
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 1604, USA
    J Nat Prod 72:1637-42. 2009
  5. pmc Antineoplastic agents. 573. isolation and structure of papilistatin from the papilionid butterfly Byasa polyeuctes termessa
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, PO Box 871604, Tempe, Arizona 85287 1604, USA
    J Nat Prod 73:164-6. 2010
  6. ncbi Culturability and secondary metabolite diversity of extreme microbes: expanding contribution of deep sea and deep-sea vent microbes to natural product discovery
    Robin K Pettit
    Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 2404, USA
    Mar Biotechnol (NY) 13:1-11. 2011
  7. pmc Antineoplastic agents 582. Part 1: Isolation and structure of a cyclobutane-type sesquiterpene cancer cell growth inhibitor from Coprinus cinereus (Coprinaceae)
    George R Pettit
    Cancer Research Institute, Department of Chemistry and Biochemistry, Arizona State University, PO Box 871604, Tempe, AZ 85287 1604, USA
    Bioorg Med Chem 18:4879-83. 2010
  8. pmc Small-molecule elicitation of microbial secondary metabolites
    Robin K Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 2404, USA
    Microb Biotechnol 4:471-8. 2011
  9. pmc Antineoplastic agents. 592. Highly effective cancer cell growth inhibitory structural modifications of dolastatin 10
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P O Box 871604, Tempe, Arizona 85287 1604, United States
    J Nat Prod 74:962-8. 2011
  10. pmc Antineoplastic agents. 590. X-ray crystal structure of dolastatin 16 and syntheses of the dolamethylleuine and dolaphenvaline units
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, PO Box 871604, Tempe, Arizona 85287 1604, United States
    J Nat Prod 74:1003-8. 2011

Scientific Experts

Detail Information

Publications19

  1. ncbi Stylopeptide 2, a proline-rich cyclodecapeptide from the sponge Stylotella sp
    Mary R Brennan
    Gustaf H Carlson School of Chemsitry and Biochemistry, Clark University, Worcester, Massachusetts 01610, USA
    J Nat Prod 71:453-6. 2008
    ..The structural assignment was based on HRMS collision-induced dissociation tandem mass spectrometry (CID MS/MS), NMR spectroscopic data, and amino acid analysis, which led to assignment of the absolute configuration...
  2. pmc Antineoplastic agents. 595. Structural modifications of betulin and the X-ray crystal structure of an unusual betulin amine dimer
    George R Pettit
    Department of Chemistry and Biochemistry, Arizona State University, P O Box 871604, Tempe, Arizona 85287 1604, United States
    J Nat Prod 77:863-72. 2014
    ..Significant cancer cell growth inhibition was found for 4, 8, 9, 15/16, 19, 20, 24, and 26, which further defines the utility of the betulin scaffold...
  3. pmc Isolation and structures of axistatins 1-3 from the Republic of Palau marine sponge Agelas axifera Hentschel
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P O Box 871604, Tempe, Arizona 85287 1604, USA
    J Nat Prod 76:420-4. 2013
    ..All of the isolated compounds were found to be moderate inhibitors of cancer cell growth. Axistatins 1-3 (1-3), formamide 4, and agelasine F (6) also exhibited antimicrobial activity...
  4. pmc Antineoplastic agents. 579. Synthesis and cancer cell growth evaluation of E-stilstatin 3: a resveratrol structural modification
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 1604, USA
    J Nat Prod 72:1637-42. 2009
    ..Deprotection of the Z-silyl ether 13 gave E-stilstatin 3 (3a) as the exclusive product. The structure and stereochemistry of 3a was confirmed by X-ray crystal structure determination...
  5. pmc Antineoplastic agents. 573. isolation and structure of papilistatin from the papilionid butterfly Byasa polyeuctes termessa
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, PO Box 871604, Tempe, Arizona 85287 1604, USA
    J Nat Prod 73:164-6. 2010
    ..Against a panel of six human and the murine P388 leukemia cancer cell lines, papilistatin exhibited cancer cell growth inhibition with GI(50)'s of 0.093-3.5 microg/mL. Papilistatin was also found to have antibacterial activity...
  6. ncbi Culturability and secondary metabolite diversity of extreme microbes: expanding contribution of deep sea and deep-sea vent microbes to natural product discovery
    Robin K Pettit
    Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 2404, USA
    Mar Biotechnol (NY) 13:1-11. 2011
    ....
  7. pmc Antineoplastic agents 582. Part 1: Isolation and structure of a cyclobutane-type sesquiterpene cancer cell growth inhibitor from Coprinus cinereus (Coprinaceae)
    George R Pettit
    Cancer Research Institute, Department of Chemistry and Biochemistry, Arizona State University, PO Box 871604, Tempe, AZ 85287 1604, USA
    Bioorg Med Chem 18:4879-83. 2010
    ..The structures of compounds 2, 3, and 4 were each deduced by a combination of HRMS and 1D and 2D NMR techniques. Cyclobutane 2 led to modest inhibition of the murine P388 leukemia cell line...
  8. pmc Small-molecule elicitation of microbial secondary metabolites
    Robin K Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 2404, USA
    Microb Biotechnol 4:471-8. 2011
    ....
  9. pmc Antineoplastic agents. 592. Highly effective cancer cell growth inhibitory structural modifications of dolastatin 10
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P O Box 871604, Tempe, Arizona 85287 1604, United States
    J Nat Prod 74:962-8. 2011
    ....
  10. pmc Antineoplastic agents. 590. X-ray crystal structure of dolastatin 16 and syntheses of the dolamethylleuine and dolaphenvaline units
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, PO Box 871604, Tempe, Arizona 85287 1604, United States
    J Nat Prod 74:1003-8. 2011
    ..The X-ray crystal structures of synthetic Z-Dml and TFA-Dpv have also been completed...
  11. pmc An efficient synthetic strategy for obtaining 4-methoxy carbon isotope labeled combretastatin A-4 phosphate and other Z-combretastatins
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287 1604, USA
    J Nat Prod 73:399-403. 2010
    ..Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling...
  12. pmc Antineoplastic agents. 556. Isolation and structure of Coprinastatin 1 from Coprinus cinereus
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287 1604, USA
    J Nat Prod 73:388-92. 2010
    ..Coprinastatin 1 (1) was found to inhibit growth of the murine P388 lymphocytic leukemia cell line and the pathogenic bacterium Neisseria gonorrhoeae...
  13. pmc Application of a high throughput Alamar blue biofilm susceptibility assay to Staphylococcus aureus biofilms
    Robin K Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287, USA
    Ann Clin Microbiol Antimicrob 8:28. 2009
    ..epidermidis cannot be applied to S. aureus without first evaluating the assay's reproducibility and reliability with S. aureus biofilms...
  14. pmc In vivo activity of anprocide alone, and in vitro activity in combination with conventional antibiotics against Staphylococcus aureus and Staphylococcus epidermidis biofilms
    Robin K Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, USA
    J Med Microbiol 58:1203-6. 2009
    ..Anprocide was also synergistic in combination with bacitracin or oxacillin against some isolates of biofilm-grown S. aureus and S. epidermidis...
  15. ncbi Mixed fermentation for natural product drug discovery
    Robin K Pettit
    Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 2404, USA
    Appl Microbiol Biotechnol 83:19-25. 2009
    ....
  16. pmc Antineoplastic agents. 570. Isolation and structure elucidation of bacillistatins 1 and 2 from a marine Bacillus silvestris
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P O Box 871604, Tempe, Arizona 85287 1604, USA
    J Nat Prod 72:366-71. 2009
    ..The structures were elucidated by a combination of X-ray diffraction and mass and 2D NMR spectroscopic analyses, together with chemical degradation...
  17. pmc Antineoplastic agents. 571. Total synthesis of bacillistatin 2
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P O Box 871604, Tempe, Arizona 85287 1604, USA
    J Nat Prod 72:372-9. 2009
    ....
  18. pmc Antineoplastic agents. 552. Oxidation of combretastatin A-1: trapping the o-quinone intermediate considered the metabolic product of the corresponding phosphate prodrug
    George R Pettit
    Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P O Box 872404, Tempe, Arizona 85287, USA
    J Nat Prod 71:1561-3. 2008
    ..2 microg/mL) growth of the murine P388 lymphocytic leukemia cell line and provided a new SAR insight in the combretastatin series of naturally occurring anticancer drugs...
  19. ncbi Antineoplastic agents. 536. New sources of naturally occurring cancer cell growth inhibitors from marine organisms, terrestrial plants, and microorganisms(1a,)
    George R Pettit
    Department of Chemstry and Biochemistry, Arizona State University, Tempe, Arizona 85287 2404, USA
    J Nat Prod 71:438-44. 2008
    ....