In Support of ICAN's Special Initiatives to Enhance Natural Products Drug Discovery

Exceptional and Continuing Advances in Anticancer Drug Discovery and Development toward Improving Human Cancer Treatment

by

Regents Professor George Robert Pettit
The Cancer Research Group, Arizona State University
and Chairman, ICAN Scientific Advisory Council (1997-present)

Two weeks following the appointment of this writer in 1957 as an Assistant Professor of Chemistry at the University of Maine, he began a formal collaboration with the U.S. National Cancer Institute (NCI) that has continued to the present. The general severity and lethal nature of cancer and the paucity of useful treatment methods had early captured his attention, and he decided as a student to attempt discovery of potentially curative anticancer drugs. At the University of Maine, we began an intense program directed at the discovery and/or development of new plant and animal (cancer inhibitory toad venom bufadienolide constituents) anticancer constituents combined with total syntheses and structural modifications. At the same time, a parallel program was pursued concerned with developing new syntheses of such antineoplastic substances.

In the period from 1957-1965, we developed the first practical reduction of certain esters to ethers that expanded to the first syntheses of oxa-steroids for anticancer evaluations and by other methods the first syntheses of steroidal peptides for the same reasons. Meanwhile, research concerned with the chemistry of anticancer bis(2-haloethyl) amines was undertaken that eventually provided the new heterocyclic system of DABIS maleate that the EORTC advanced to phase I human cancer clinical trials. Another major effort in this period was directed at developing practical synthetic sequences for the degradation of lanosterol to 14α-methyl steroids of interest for possible implication in hormone-dependent cancers. For these purposes, syntheses were achieved for 14α-methyl testosterone, 14α-methyl estranges and, for example, 14α-methyl progesterone.

With the transfer of our research group in 1965 to the Department of Chemistry at Arizona State University, research directed at the synthesis of antineoplastic peptide alkaloids, nucleopeptides, and the cancer cell growth inhibitory (predicted and later confirmed) steroidal bufadienolide toad venom constituents were continued and resulted in the syntheses of emetine peptides and total synthesis of, for example, isobufalin methyl ester, bufalin, resibufogenin, bufotalien, marinobufagin, marinobufotoxin, cinobufagin, 14α- and 14β-artebufogenin, telocinobufagin, 15β-hydroxybufalin, and bufotoxin. Presently, resibufogenin is sold in Asia to increase the force of heart contraction (cardiotonic) and marinobufagen is of high interest in the etiology of preeclampsia in pregnancy.

By 1973, our cancer research group was officially recognized by the Arizona Board of Regents as the ASU-Cancer Research Laboratory and by 1975 as the ASU Cancer Research Institute (ASU-CRI). Meanwhile, important research begun in 1957 at the University of Maine focused on discovery of plant anticancer constituents became increasingly productive at Arizona State. Highlights include the discovery, isolation, structural elucidation and some total syntheses of a series (some examples follow) with cell growth inhibitory and/or antineoplastic activity: the amoorastatins, aphanastatin, the bauhiniastatins, the combretastatins (the A-4 and A-1 are in human cancer clinical trials), the lychnostatins, the meliastatins, multigilin, multistatin, narcistatin, the nootkastatins, palstatin, pancratistatin (advanced preclinical development), pedilstatin, the phyllanthostatins (1 and 2 completed phase I clinical trials), radiatin, rolliniastatins, the sansevistatins, and the schleicherastatins. Highlights of parallel studies of microorganism anticancer constituents include the isolation and structural elucidations of carminomycin (in clinical use), kitastatin 1, the labradorins, montanastatin, and the streptomyces antitumor antibiotic 593A (clinical trials by the NCI), as well as convenient syntheses of the streptomyces anticancer drugs DON and azotomycin.

By 1965-66, owing to increased resources (especially support from the U.S. National Cancer Institute), we were able to begin pioneering two vast and essentially unexplored natural product areas for the potential discovery of new anticancer drugs; namely, the constituents of terrestrial arthropods such as insects and marine organisms. Both promising fields had been of personal long-standing interest (from about 1955).With the arthropods, initial emphasis was placed on the class Insecta and we soon found that such arthropods did offer promise of providing antineoplastic constituents. Subsequently, the first insect antineoplastic constituents were isolated from Asian butterflies, an Asian beetle, Allomyrina dichotomus, the yellow jacket Vespula pennsylvanica, and more recently a Texas grasshopper that yielded a new source of our important anticancer drug, pancratistatin.

By 1968, we were able to show from a broad (world-wide) geographical selection of marine invertebrates and vertebrates that both held the potential for eventual discovery of completely new types of anticancer drugs. The intervening period has witnessed the accelerating discovery of potentially important anticancer drugs and other types of drugs based on marine animal and microorganism constituents. Some of our major accomplishments in this vitally important and relatively new area of drug discovery and development include the isolation and structural elucidation of the following cell growth inhibitory and/or antineoplastic marine animal components beginning in 1968-73: aplysistatin, the axinostatins, the bryostatins (in extensive human cancer clinical trials), the cephalostatins, the cribrostatins, the dolastatins (in human cancer clinical trials), the geodiastatins, halistatin, the halicondrin series, the hemibastadins, hymenistatin 1, the hystatins, the irciniastatins, lytechnistatin, the palystatins, the sesterstatins, the spongistatins, the sphyrnastatins, stichostatin 1, the strongylostatins, and the turbostatins. Some of these series comprise twenty or more related anticancer active molecules.

Of the preceding insect, marine organism, microorganism, and terrestrial plant antineoplastic constituents, including structural modifications (by our ASU-CRI group), nine are currently undergoing human cancer clinical trials. Another three in present clinical trials represent structural modifications such as ectienascidin 742 based on the halichondrin/halistatin series and developed by other research groups. Presently, we have another twenty at various stages of development that justify rapid preclinical development. As further overwhelming evidence for the necessity of giving top priority to discovery and development of naturally occurring anticancer (and other very effective agents for a large spectrum of medical problems) drugs we have uncovered a large number of other natural product anticancer leads awaiting further research. Most importantly, many cancer victims have been and are now benefiting from our anticancer drug discoveries.

In parallel, many of the naturally occurring small molecule drugs we have discovered have the potential for being developed for other serious medical problems and can be illustrated briefly by combretastatin A-4 phosphate (in phase 2 trials for macular degeneration), narcistatin (in preclinical development for arthritis), and pancratistatin (antiviral).

Very little of the preceding advances in the chemistry of natural products, organic chemistry, medicinal chemistry, and cancer research would have occurred without the extraordinary contributions of my doctoral level colleagues (some 200 postdoctoral, faculty research associate, and research professors), doctoral candidates (over 70), key staff (including expedition divers and other staff), and a large number of undergraduate assistants. All, including my expert colleagues in the U.S. National Cancer Institute, other universities and institutes, receive my warmest thanks and appreciation.

References: For leading references, please consult the following:

G. R. Pettit, R. Tan, R. K. Pettit, T. H. Smith, S. Feng, D. L. Doubek, L. Richert, J. Hamblin, C. Weber, and J-C. Chapuis, "Antineoplastic Agents 560. Isolation and Structure of Kitastatin 1 from an Alaskan Kitasatospora sp.," J. Nat. Prod., 70, 1069-1072, (2007).

G. R. Pettit, N. Melody, and D.L. Herald, J.C. Knight,and J-C Chapuis, "Antineoplastic Agents 550. Synthesis of 10b (S)-epipancratistatin from (+)- Narciclasine," J. Nat. Prod., 70, 417 (2007).

H. L. LaMarca, C. A. Morris, G. R. Pettit, T. Nogawa, J. B. Puschett, "Marinobufagenin Impairs First Trimester Cytotrophoblast Differentiation, Placenta," 27, 984-988, (2006).

G.R. Pettit, Y. Meng, D.L. Herald, J.C. Knight, and J.F. Day, "Antineoplastic Agents 553. The Texas Grasshopper Brachystola manga," J. Nat. Prod., 68, 1256-1258 (2005).

G. R. Pettit, F. Hogan and D. L. Herald, “Synthesis and X-Ray Crystal Structure of the Dolabella auricularia Peptide Dolastatin 18,” J. Org. Chem., 69,4019-4022 (2004).

Haefner, B. Drugs from the Deep: Marine Natural Products as Drug Candidates. DDT, 8, 536-544 (2003).

G. R. Pettit, "Evolutionary Biosynthesis of Anticancer Drugs," in Anticancer Agents: Frontiers in Cancer Chemotherapy, ed. By I. Ojima, G. D. Vite, and K-H. Altmann, American Chemical Society,Washington, DC, 2001, pp. 16-42.



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