Tags: Pharmaceuticals, Carlos Alberto M. Fraga, Encyclopedia of Life Support Systems, Eliezer J. Barreiro, natural products, Lidia M. Lima, PHYTOCHEMISTRY, drug discovery, medicinal chemistry, Rio de Janeiro, hallucinogenic plants, natural product, drug candidate, compound, therapeutic application, Gardner A. D., Kirkpatrick P., article present, Barreiro E. J., A Borchardt J. K., Fraga C. A. M., J. Cancer, lead compound, rational drug design, PHARMACOGNOSY, Universidade Federal, drug candidates, Rio de Janeiro, RJ, Brazil Keywords, Jennings M. A., De Clercq E., molecular modification, synthetic drugs, Zimmerman D. M., Barreiro, Carlos Alberto Manssour Fraga, Federal University, Lidia M. Lima Thomas C. J., Pharmaceutical Chemistry, Professor Barreiro, Alberto Manssour Fraga, penicillin discovery, Drug Discov, synthetic drug, Goldstein J. L., chemistry space, competitive inhibitor, Lidia M. Lima Georgoulias V., Federal University of Rio de Janeiro, Barreiro E. J. Fraga C. A. M., Lidia M. Lima Corey E. J., Flores M. Francesca, U M Chain E.
Content: PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima THE ORIGIN OF PHARMACEUTICALS Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima Laboratуrio de Avaliaзгo e Sнntese de Substвncias Bioativas (LASSBio®) Faculdade de Farmбcia, Universidade Federal do Rio de Janeiro, CCS, Cidade Universitбria, ZIP 21944-910 Rio de Janeiro, RJ, Brazil Keywords: natural products; medicinal chemistry, lead-compound, drug-candidates Contents 1. Medicinal Chemistry definition and the role of lead-compound in drug discovery 2. Natural products as medicines and drugs candidates 2.1. Plants as a source of drugs S 2.2. Microorganisms as a source of drugs S S 2.3. Marine as a source of drugs 3. Conclusions L R Acknowledgements Glossary O E Bibliography E T Summary ­ AP The importance of natural products in therapeutics has been generally recognized from immemorial time. The Amerindians' knowledge of hallucinogenic plants used for their O H religious rituals, as well as the aphrodisiac properties of several potions prepared from several plant species, have accompanied man for millennia. Throughout the ages, the C C search for the well-being and for the pleasure has always stimulated man to approach nature, teaching him to make good use of plants and their components. Although plants S E and microorganisms remain a major source of new drugs, natural products from marine E sources have been actively investigated in recent decades. In fact, the possibility of L finding new medicines from natural sources is one of the more old man's activities and N P represents one of the most mentioned reasons for preserving biodiversity. The use of natural products as drug found several examples in therapeutics, as well as their use as U M an important template for molecular modification, being a crucial source of new original structural patterns that represents an authentic "molecular inspiration" for the design of A new drugs. This chapter will cover the main natural products from plants, S microorganisms and from marine sources that were developed to medicines and those that historically contributed as lead-compound for designing and discovery of more active and safer drug candidates. 1. Medicinal Chemistry Definition and the Role of the Lead-Compound in Drug Discovery The Committee of the International Union of Pure and Applied Chemistry (IUPAC), recently, defined Medicinal Chemistry as: "a chemistry-based discipline, also involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification and preparation of biologically active ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima compounds, the interpretation of their mode of interaction at the molecular level, the construction of their structure-activity relationships, and the study of their metabolism". The interdisciplinarity between Chemistry and Biology, essential for medicinal chemistry, was brilliantly recognized by Arthur Kornberg, Nobel Laureate in Physiology and Medicine in 1959, when he said in the Congress of the American Association for the Advance of Science, in 1987: "We have the paradox of the two cultures, chemistry and biology, growing further apart even as they discover more common ground. For the chemists, the chemistry of biological systems is either too mundane or too complex". By harmonizing these two "science", seemingly distinct conditions necessary and essential to the interaction of medicinal chemists, pharmacologists, toxicologists, biochemists, and so on, lead to the discovery or designing new molecular patterns, which under particular conditions could be considered as a lead-compound or a drug candidate. SS S A lead-compound is considered to be the prototype identified with equilibrium between the pharmacodynamic and pharmacokinetics properties, in order to assure it L R pharmacological activity in animal models (in vivo). Later, it needs to pass by several toxicological studies aiming to determine its therapeutic index, cellular and tissue O E damages, carcinogenic and teratogenic profiles. Finalized this toxicological step, the E T best lead-compound can be now considered a drug candidate. P Not rare, the identified lead-compound (LC) needs a step of optimization in order to ­ adjust or improve some particular characteristics of the LC in the pharmacodynamic A (PD) and/or pharmacokinetic (PK) phases. The optimization step consists in the rational O H design of specific molecular modifications to be introduced in the structure of the lead- compound, which often are performed by applying classic medicinal chemistry C C strategies, like bioisosterism and molecular simplification, and can be aided by the use of molecular modeling. The Figure 1 illustrated the LC approach of the rational drug USNAEMSPLE design process. Figure 1. The lead-compound approach in the complex process of rational discovery of new drugs. ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima Each drug design (DD) program is unique and setbacks are not rare, making it difficult to predict accurately the duration or costs and it is now well accepted that predicted eventual toxicity in the very early stages seen to be important to identify the level of safety of this new drug candidate. Modern DD became a hybrid process, no more linear as some few years ago were considered, and efforts typically emerge in order to obtain new lead-compounds in a shorter time, with lower cost. In this process, different strategies can be employed, like the so called hyphen-strategies, resulting from the combination of two specific technologies (e.g. HTS-combinatorial chemistry), that are especially common in pharmaceutical industry laboratories or in high-tech small companies. It is necessary to recognize that DD process represents an important example, maybe the most relevant, of the critical role of the basic science from different health disciplines to go gradually on a specific sequential of tasks to ­ if successfully ­ culminate in a new S drug for the treatment of a human disease. This overall pathway is well-structured and S S start from the carefully selection of the drug target, applying the classical strategy of rational drug design named physiological approach. Besides, it can be initiated by L R bioprospecting natural products from different sources, leading to the identification of a new lead compound, that could be later modified in order to optimizing its structure, O E activity, selectivity, toxicity and so on, until it can be considered an authentic drug E T candidate for pre-clinical and clinical trials. P 2. Natural Products as Medicines and Drugs Candidates ­ A The importance of natural products in therapeutics has been generally recognized from O H immemorial time. The Amerindians' knowledge of hallucinogenic plants used for their religious rituals, as well as the aphrodisiac properties of several potions prepared from C C various plant species, have accompanied man for millennia. S Plants, fungi, insects, marine organisms and bacteria represent a rich sources of E therapeutically useful compounds. Great part of the drugs in clinical use is of natural E L origin or was developed inspired on modification of a natural scaffold. A recent survey N of all drugs approved worldwide between 1981 and 2006 pointed out that 34% of all P small-molecule drugs are natural products or their direct semisynthetic derivatives. The U impact of natural products is even more profound among drugs that are used to treat M severe and/or life-threatening diseases such as cancer and infectious diseases. Among A all approved small-molecule anticancer drugs (total 155), 47% are either natural S products or direct semisynthetic derivatives. Similar dominance of natural products is observed among the anti-infective compounds, and amazingly >75% out of approved antibacterials are natural products or their semisynthetic derivatives (74 out of 98). In spite of various strategies and methodologies currently available to design, synthesize and discover new medicines, natural products continues to represent an important and privileged starting material for drug discovery. In general, one of the greatest challenges for natural product based drug discovery has been their structural complexity and low synthetic feasibility. Otherwise, they have quite distinct structural characteristics from synthetic molecules. For example, when ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima analyzed by either a size-independent `chemistry space filter' or `support-vectormachine' approach, natural products exhibit better scores of `druglikeness' than synthetic compounds. Further, natural products contain on average twice as many oxygen atoms and three times fewer nitrogen atoms than synthetic drug molecules. They also contain a slightly higher number of hydrogen-bonding donors than do synthetic drugs. Natural products contain approximately four times more chiral centers and far fewer aromatic rings, a fact which may engender upon natural products better selectivity when binding to stereo-defined sites. - S TO ACCESS ALL THE 38 PAGES OF THIS CHAPTER, S S Visit: OL ER Bibliography E T Barreiro E. J. Fraga C. A. M. (2008) Quнmica Medicinal - As Bases Moleculares da Aзгo dos Fбrmacos, P 2nd ed., ArtMed, Porto-Alegre, BR, 536p. [The book is recommended to scientists interested in drug ­ discovery and discusses the molecular basis of drug action.] A Borchardt J. K. (1999) Combinatorial biosynthesis: Panning for pharmaceutical gold. Modern Drug Discovery 2, 22-29. [The article discusses the use of combinatorial biosynthesis technology in the O H construction of libraries of pharmaceutical interest.] Brown M. S., Goldstein J. L. (1986) A receptor-mediated pathway for cholesterol homeostasis. Science C C 232, 34­47. [The article describes the role of cell surface receptors in the cholesterol homeostasis.] S Carriere F., Renou C., Ransac S., Lopez V., DeCaro J., Ferrato F., DeCaro A., Fleury A., SanwaldE Ducray P., Lengsfeld H., Beglinger C., Hadvary P., Verger R., Laugier, R. (2001) Inhibition of E gastrointestinal lipolysis by orlistat during digestion of test meals in healthy volunteers. Am. J. Physiol. L Gastrointest. Liver Physiol. 281, G-16-G28. [The article present clinical study provides the first N P comprehensive overview of test meal lipolysis in healthy human volunteers, in the presence and absence of orlistat.] U M Chain E. (1979) The early years of the penicillin discovery, Trends Pharmacol. Sci. 1, 6-11. [The article describes the history of penicillin discovery.] A Chain E., Florey H. W., Gardner A. D., Heatley N. G., Jennings M. A., Orr-Ewing J., Sandres A. G. S (1940) Penicilin as chemotherapeutic agent. Lancet 2, 226-228. [The article describes and discusses the therapeutic application of penicillin.] Clamp A. R., Blackhall F. H., Vasey P., Soukop M., Coleman R., Halbert G., Robson L., Jayson G. C. (2003) Phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma. Brit. J. Cancer 89, 1152­1154. [The article describes the results of bryostatin-1 Phase II trial in recurrent epithelial ovarian carcinoma.] Collins P. W. (1993) Misoprostol, In: Chronicles of Drug Discovery, ACS, Washigton, USA, vol.3, p.101-124. [This chapter describes the history of misoprostol discovery.] Conlin A., Fornier M., Hudis C., Kar S., Kirkpatrick P. (2007) Ixabepilone. Nat. Rev. Drug Discov. 6, 953-954. [The article is a review about the first member of the epothilone family of anticancer agents to be approved.] ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima Corey E. J., Kьrti L., Czakу B. (2007) Molecules and Medicines, Wiley, USA, 254p. [The book provides a completely integrated look at chemistry, biology, drug discovery, and medicine. It delves into the discovery, application, and mode of action of more than one hundred of the most significant molecules in use in modern medicine.] Crabbй P. (1977) Prostaglandin Research, Academic Press, NY, USA, p.269. [This book describes an overall view on various aspects of prostaglandin]. Cragg G. M., Newman D. J. (2004) A tale of two tumor targets: topoisomerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy, J. Nat. Prod. 67, 232-244. [The article is a review about the seminal discoveries of camptothecin and Taxol by Wall and Wani.] Cuevas C., Pйrez M., Martin M. J., Chicharro J. L., Fernandez-Rivas C., Flores M. Francesca, A., Gallego P., Zarzuelo M., de la Calle F, Garcia J., Polanco C., Rodrнguez I., Manzanares I. (2000) Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B., Org. Lett. 2, 2545-2548. [The article describes an efficient new process for the synthesis of ecteinascidin.] Damayanthi Y., Lown. J. W. (1998) Podophyllotoxins: current status and recent developments. Curr. Med. Chem. 5, 205-252. [The article reviews the progress of podophyllotoxins application, mechanism of S action and the structure-activity relationship.] S S de Sa Alves F. R., Barreiro E. J., Fraga C. A. M. (2009) From Nature to Drug Discovery: The Indole Scaffold as a `Privileged Structure'. Mini Reviews in Medicinal Chemistry 9, 782-793. [The article L R reviews the role of indole as privileged structure to drug design and discovery.] De Souza M. V. (2004) (+)-discodermolide: a marine natural product against cancer. The Scientific World O E Journal 4, 415-36. [This review covers the history, biological activity, total synthesis, and synthetic E T analogs of (+)-discodermolide.] Dewick P. M. (2009) Medicinal Natural Products: A Biosynthetic Approach, 3rd ed. Wiley, NY, USA, P 550p. [The book provides a comprehensive and balanced introduction to natural products from a ­ biosynthetic perspective, focusing on the metabolic sequences leading to various classes of natural A products.] O H Eisenreich W., Kupfer E., Stohler P., Weber W., Bacher A. (2003) Biosynthetic origin of a branched chain analogue of the lipase inhibitor, lipstatin, J. Med. Chem., 46, 4209-4212. [The article describes the three putative intermediates in the biosynthesis of the lipase inhibitor lipstatin.] C C Endo A., Tsujita Y., Kuroda M., Tanzawa K. (1977) Inhibition of cholesterol synthesis in vitro and in S vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A E reductase. Eur. J. Biochem. 77, 31­36. [The article describes experimental evidence that E hypocholesterolemic activity of ML-236A and ML-236B is owing largely to specific inhibition of hepatic L cholesterol synthesis.] N P Fang W-S., Liang X-T. (2005) Recent progress in structure activity relationship and mechanistic studies of Taxol analogues. Mini Rev. Med. Chem. 5, 1-12. [The article discusses the structure activity U M relationship (SAR) and mechanism of action of paclitaxel and its analogues.] Field H. J., De Clercq E. (2004) antiviral drugs ­ a short history of their discovery and development. A Microbiology Today 31, 58-61. [The article briefly describe the history of several antiviral drugs S discovery and development.] Foye W. O., Lemke T. L., Williams D. A. (2007) Principles of Medicinal Chemistry, 6th ed. Lippincott Williams & Wilkins, Baltimore, USA, 1377p. [In this sixth edition text has been fully revised and updated to meet the changing curricula of medicinal chemistry courses. The book deals with the concepts of medicinal chemistry by the look of therapeutic classes.] Fusetani N. (2000) Drugs from the Sea, Karger AG, Basel, Switzerland, 2000, 158p. [The book covers the discovery, development and production of drugs from marine bacteria, fungi, microalgae, sponges and opisthobranch mollusks.] Gaudiano G., Koch T. H. (1991) Redox chemistry of anthracycline antitumor drugs: a use of adaptive radials as tools for its elucidation and control. Chem. Res. Toxicol. 4, 2-16. [The article describes the involvement of quinone methides and semiquinone methides as viable transient intermediates for covalently linking anthracycline aglycons to biological macromolecules.] ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima Georgoulias V. (2002) Docetaxel (Taxotere) in the treatment of non-small cell lung cancer. Curr. Med. Chem. 9, 869-877. [The article describes the effect of docetaxel, as single agent or in combination, in the treatment of non-small cell lung cancer.] Grabowski K., Schneider G. (2007) Properties and architecture of drugs and natural products revisited. Curr. Chem. Biol. 1, 115-127. [The article describes that computational chemical biology can assist in finding suitable molecular entities in collections of natural products for drug discovery.] Gunasekera S. P., Gunasekera M., Longley R. E., Schulte G. K. (1990) Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodermia dissolute. J. Org. Chem. 55, 4912-4915. [The article describes the structural elucidation of Discodermolide and its immunosuppressive and cytotoxic activities.] Hale K. J., Hummersone M. G., Manaviazar S., Frigerio M. (2002) The chemistry and biology of the bryostatin antitumour macrolides. Nat. Prod. Rep.19, 413­453. [The article reviews the chemistry and biologic aspects of bryostatin and related compounds.] Hargittai I. (2002) The road to Stockholm: Nobel Prizes, science, and scientists, Oxford University Press, 370p. [The book describes the history of the Nobel prizes for science, first awarded in 1901.] S Hecht S. M. (2000) Bleomycin: new perspectives on the mechanism of action, J. Nat. Prod. 63, 158-168. S S [The article is an invited review about bleomycin group antitumor antibiotics.] Hofle G., Bedorf N., Steinmetz H., Schumburg D., Gerth K., Reichenbach H. (1996) Epothilone A and B- L R -novel 16-membered macrolides with cytotoxic activity: isolation, crystal structure, and conformation in solution. Angew. Chem., Int., Ed. Engl., 35, 1567-1569. [The article describes the process of isolation, O E characterization and the cytotoxic activity of epothilones A and B.] E T Hoshino T., Okamoto M., Sakazaki Y., Kato S., Young H. A., Aizawa H. (2009) Role of proinflammatory cytokine IL-18 and IL-1{beta} in bleomycin-induced Lung injury in humans and mice. P Am. J. Respir. Cell Mol. Biol. 41, 661-670. [The article describes the role of the proinflammatory ­ cytokines IL-18 and IL-1 in the mechanism of bleomycin-induced lung injury.] A Johnson I. S., Armstrong J. G., Gorman M., Burnett-Jr J. P. (1963) The vinca alkaloids: a new class of O H oncolytic agents. Cancer Res 23, 1390-1427. [The article discusses the problems and obstacles encountered in obtaining a full realization of the clinical efficacy of vinca alkaloids and describe their potential clinical application.] C C Katzung B. G. (2004) Basic and Clinical Pharmacology, 9th ed., Lange, 1088p. [The book provides a S complete, authoritative, current, and readable pharmacology textbook for students in health sciences.] E Kesado T., Hashizume T., Asahi Y. (1980) Antibacterial activities of a new stabilized thienamycin, NE L formimidoyl thienamycin, in comparison with other antibiotics. Antimicrob. Agents Chemother. 17, 912­ 917. [The article describes the in vitro activity of a new derivative of thienamycin against 46 laboratory N P reference strains and 2,158 clinical isolates of gram-positive and Gram-negative bacteria and compares the results with cefoxitin, cefazolin, carbenicillin, and amikacin.] U M Kijjoa A., Sawangwong P. (2004) Drugs and cosmetics from the sea. Mar. Drugs 2, 73-82. [The article reviews the potential of marine natural products for industrial development as pharmaceuticals, A cosmetics, nutritional supplements, molecular probes, fine chemicals and agrochemicals.] S Kozikowski P., Tьckmantel W. (1999) Chemistry, pharmacology, and clinical efficacy of the Chinese nootropic agent Huperzine A. Acc. Chem Res. 32, 641-650. [The article reviews the chemical and pharmacological properties of huperzine-A and describes the discovered of more potent huperzine analogues.] Lee M. R. (2005) Curare: the South American arrow poison. J R Coll Physicians Edinb 35, 83­92. [The article describes the history of curare and d-tubocurarine.] Li J. W-H, Vederas J. C. (2009) Drug Discovery and natural products: end of an era or an endless frontier? Science 325,161-165 [The article is a review about the role of natural product in drug discovery process, using modern industrial paradigm.] Lima L. M., Barreiro E. J. (2005) Bioisosterism: A Useful Strategy for Molecular Modification and Drug Design. Curr. Medl Chem. 12, 23-49. [The article is a review about bioisosterism and its application.] ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima Lown J. W. (1993) Anthracycline and anthraquinone anticancer agents: current status and recent developments. Pharmacol. Ther. 60, 185­214. [The article reviews the discovery of anthracyclines and the elucidation of their several mechanisms of action and efforts towards improvement of their therapeutic efficacy.] Mann J., Davidson R. S., Hobbs J. B., Banthorpe D. V., Harborne J. B. (1994) Natural products: Their chemistry and biological significance, Wiley, NY, USA. 455p. [The book provides information on chemical structures, chemical groups, biosynthesis, occurrence, and synthesis of natural compounds isolated from plants, animals and microorganisms.] Marco J. L., Carreiras M. C. (2003) Recent developments in the synthesis of acetylcholinesterase inhibitors. Mini Rev. Med. Chem. 3, 518-524. [The article describes the acetylcholinesterase and butyrylcholinesterase inhibitory activities of synthetic tacrine analogues.] Maurois A. (1959) La vie de Sir Alexander Fleming, Hachette, Paris. [Translation by Hopkins published as The Life of Sir Alexander Fleming, Discoverer of Penicillin, Dutton (New York, NY), 1959, same translation published as Fleming, the Man Who Cured Millions, Methuen (London, England), 1961.] Mitscher L. A. (2005) Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents. S Chem. Rev. 105, 559­92. [The article reviews the history, the chemistry and activity of bacterial topoisomerase inhibitors.] S S Mitsuya H., Weinhold K., Furman P., St Clair M., Lehrman S., Gallo R., Bolognesi D., Barry D., Broder L R S. (1985) 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. O E Proc. Natl. Acad. Sci. USA 82, 7096­7100. [The article describes the in vitro pharmacological profile of the antiviral BW A509U.] E T Molinski T. F., Dalisay D. S., Lievens S. L., Saludes J. P. (2009) Drug development from marine natural P products. Nat. Rev. Drug Discov. 8, 69-85. [The article reviews the history of drug discovery from marine ­ natural products and examines the factors that contribute to new discoveries and the difficulties associated A with translating marine-derived compounds into clinical trials.] Morris P. G., Fornier M. N. (2009) Ixabepilone and other epothilones: microtubule-targeting agents for O H metastatic breast cancer. Clin. Adv. Hematol. Oncol. 7, 115-122. [The article reviews the epothilone and its analogues activity in a variety of tumors, and highlights ixabepilone as the only one licensed by FDA C C for the treatment of metastatic breast cancer.] Muraleedharan K. M., Avery M. A. (2009) Progress in the development of peroxide-based anti-parasitic S E agents. Drug Discovery Today 14, 793-803. [The article reviews the semisynthetic and synthetic analogues of artemisinin and highlights the recent trends and avenues for future research.] E L Nakao Y., Shiroiwa T., Murayama S., Matsunaga S., Goto Y., Matsumoto Y., Fusetani N. (2004) N P Identification of renieramycin A as an antileishmanial substance in a marine sponge Neopetrosia sp. Mar. Drugs 2, 55-62. [The article describes the use of bioassay-guided fractionation of an active sponge U Neopetrosia sp. to afford an active antileishmanial compound identified as renieramycin A.] M Newman D. J. (2008) Natural Products as Leads to Potential Drugs: An Old Process or the New Hope for A Drug Discovery. J. Med. Chem. 51, 2589-2599. [The article is a miniperspective that attempt to demonstrate the use of information from nature and from compounds that though formally "synthetic" are S derived from natural products, or mimic natural product topographies, can be used in a variety of ways to lead to novel structures with therapeutic potential.] Newman D. J., Cragg G. M. (2004) Marine natural products and related compounds in clinical and advanced preclinical trials. J. Nat. Prod. 67, 1216-1238. [The article is a review about bioactive marine products and related compounds and their preclinical and clinical studies.] Newman D. J., Cragg G. M. (2007) Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461-477. [The article is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003 and highlight the principal therapeutic areas beneficiated by natural product drugs and related derivatives.] O'Neill P. M., Barton V. E., Ward S. A. (2010) The molecular mechanism of action of artemisinin--The debate continues. Molecules 15, 1705-1721. [The article reviews the mechanism of action of artemisinin ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima and discusses the recent evidence explaining its bioactivation and its potential molecular targets in the chemotherapy of malaria and cancer.] O·mura S., Fujimoto T., Otoguro K., Matsuzaki K., Moriguchi R., Tanaka H., Sasaki Y. (1991) Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells. J. Antibiot. 44, 113-116. [The article is a communications to the Editor, describing the discovery of a novel compound designated lactacystin isolated from the cultured broth of a Streptomyces strain.] Oberlies N. H., Kroll D. J. (2004) Camptothecin and taxol: historic achievements in natural products research. J. Nat. Prod. 67, 129-135. [The article is an invited review about the discovery of two first-inclass life-saving chemotherapeutic agents: camptothecin and taxol, by the research team of Dr. Monroe E. Wall and Dr. Mansukh C. Wani.] Rajendran V., Saxena A., Doctor B. P., Kozikowski A. P. (2002) Synthesis of More Potent Analogues of the Acetylcholinesterase Inhibitor, Huperzine B. Bioorg. Med. Chem. Lett. 12, 1521-1523. [The article describes the synthesis and acetylcholinesterase inhibition activity of analogues of huperzine-B.] Rinehart K. L. (2000) Antitumor compounds from tunicates. Med. Res. Rev. 20, 1­27. [The article is a review about six marine-derived compounds, derived from tunicates, that have reached clinical trials as S antitumor agents.] S S Rinehart K. L., Holt T. G., Fregeau N. L., Stroh J. G., Keifer P. A., Sun F., Li L.H., Martin D. G. (1990) Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumor agents from the Caribbean tunicate L R Ecteinascidia turbinate. J. Org. Chem. 55, 4512­4515. [The article describes the isolation from the colonial tunicate Ecteinascidia turbinate of Ecteinascidins 729, 743,745,759A, 759B, and 770 with potent O E in vivo antitumor activity.] E T Schmidtko A., Lцtsch J., Freynhagen R., Geisslinger G. (2010) Ziconotide for treatment of severe chronic pain. The Lancet 375, 1569-1577. [The article describes an overview of the benefits and limitations of P intrathecal ziconotide treatment and reviews the potential future developments in this new drug class.] ­ Scott L. J., Goa K. L. (2000) Galantamine: a review of its use in Alzheimer's disease. Drugs. 60, 1095A 1122. [The article is a review about the pharmacological profile of galantamine, one of the first-line pharmacological treatments in patients with mild to moderate Alzheimer's disease.] O H Sever P. S., Dahlцf B., Poulter N. R., Wedel H., Beevers G., Caulfield M., Collins R., Kjeldsen S. E., Kristinsson A., McInnes G. T., Mehlsen J., Nieminen M., O'Brien E., Ostergren J. (2003) Prevention of C C coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than- average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering S E Arm (ASCOT-LLA): a multicentre randomized controlled trial. The Lancet 361, 1149­1158. [The article describes benefits of atorvastatin in the primary prevention of coronary heart disease (CHD) in E L hypertensive patients.] N P Shaw S. J. (2008) The Structure Activity Relationship of Discodermolide Analogues. Mini Rev. Med. Chem. 8, 276-284. [The article reviews the structure activity relationship of marine polyketide U discodermolide and its analogues.] M Sneader W. (1985) Drug Discovery: the Evolution of Modern Medicine, Wiley, NY, USA. 435p. [This A book presents a highly readable and lively account of evolution of modern medicines.] S Steinberg D., Gotto Jr A. M. (1999) Preventing coronary artery disease by lowering cholesterol levels: fifty years from bench to bedside. JAMA 282, 2043­2050. [The article describes several evidences that support the current strategy of aggressive management of hypercholesterolemia to reduce coronary artery disease morbidity and mortality.] Taylor N. (1945) Cinchona in Java: The Story of Quinine. J Am Med Assoc. 129, 582-589. [The article describes history of the discovery of the medicinal value of the bark of the various species of the cinchona tree.] The Columbia Encyclopedia (2001-2005), Sixth Edition. Columbia University Press, Copyright ©, 3200p. [This sixth edition encompassing discoveries, crises, and other events into the twenty-first century, while maintaining comprehensive coverage of centuries past.] ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima Thomas C. J., Rahier N. J., Hecht S. M. (2004) Camptothecin: current perspectives. Bioorg. Med. Chem. 12, 1585­1604. [The article is a review that provides a detailed discussion of recent advances in the medicinal chemistry of camptothecin, a potent antitumor antibiotic.] Tsujita Y., Kuroda M., Tanzawa K., Kitano N., Endo A. (1979) Hypolipidemic effects in dogs of ML236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Atherosclerosis 32, 307­313. [The article describes the reduction of both serum cholesterol and phospholipid levels in dogs treated with ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase.] Vanhoefer U., Harstrick A., Achterrath W., Cao S., Seeber S., Rustum Y. M. (2001). Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview. J. Clin. Oncol. 19, 1501-1518. [The article reviews the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.] Vroman J. A., Alvim-Gaston M. J., Avery M. A. (1999) Current progress in the chemistry, medicinal chemistry and drug design of artemisinin based antimalarials. Curr. Pharm. Des. 5, 101-138. [The article is a review that covers developments in relation to artemisinin-based antimalarial agents.] Wall, M. E. (1993) In Chronicles of Drug Discovery; Lednicer, D., Ed.; American Chemical Society: S Washington, D.C., USA, Vol. 3, 350p. [The book offers a unique insight into the drug discovery process. A compilation of accounts describing the events leading from the initial discovery to successful S S introduction on the market of fourteen important new drugs, including RU 486 (mifepristone) and taxol are described.] L R Ward S., Lloyd J. M., Pandor A., Holmes M., Ara R., Ryan A., Yeo W., Payne N. (2007) A systematic O E review and economic evaluation of statins for the prevention of coronary events. Health Technol Assess. 11, 1-160. [The article reviews the clinical effectiveness and cost-effectiveness of statins for the primary E T and secondary prevention of cardiovascular events in adults with, or at risk of, coronary heart disease.] P Wermuth C. G., Ganellin C. R., Lindberg P., Mitscher L. A. (1998) Glossary of terms used in medicinal ­ chemistry (IUPAC recommendations 1998). Pure & Appl. Chem. 70, 1129-1143. [The article is glossary A aiming to provide in a single document a consistent terminology and concise definitions of terms covering the various aspects of medicinal chemistry.] O H Westley-Horton E., Koestner J. A. (1991) Aztreonam: a review of the first monobactam. Am. J. Med. Sci. 302, 46-49. [The article reviews the pharmacology and antimicrobial spectrum of aztreonam, the first C C synthetic monobactam to be marketed in the USA.] Zhang J., Burnell J. C., Dumaual N., Bosron W. F. (1999) Binding and hydrolysis of meperidine by S E human liver carboxylesterase. JPET 290, 314­318. [The article describes the competitive binding of meperidine and propoxyphene with human liver carboxylesterases using a spectrophotometric assay.] E L Zhang M-Q, Wilkinson B. (2007) Drug discovery beyond the `rule-of-five'. Curr. Opin Biotech. 18, 478­ N P 488. [The article describes that nearly half of all small-molecule drugs are either not used for oral administration or do not comply with the `rule-of-five' and discusses the reasons for the incompatibility U between huge industrial effort and the lower percentage of relevant drugs in clinical use.] M Zhu S., Zhang Q., Gudise C., Wei L., Smith E., Zeng Y. (2009) Synthesis and biological evaluation of A febrifugine analogues as potential antimalarial agents. Bioorg. Med. Chem. 17, 4496­4502. [The article describes the design and synthesis of new febrifugine analogues, some of them possessing a therapeutic S index over ten times superior to that of the chloroquine.] Zimmerman D. M., Gidda J. S., Cantrell B. E., Schoepp D. D., Johnson B. G., Leander J. D. (1994) Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders. J. Med. Chem. 37, 2262-2265. [The article describes the structure activity relationship of novel piperidine derivatives as selective opioid antagonist with high activity following systemic administration.] Zimmerman D. M., Nickander R., Homg J. S., Wong D. T. (1978) New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series. Nature 279, 332-334. [The article describes the structure activity relationships of some 1,3,4-trialkyl-4-phenylpiperidines that represent the first new class of pure narcotic antagonists since the discovery of naloxone.] ©Encyclopedia of Life Support Systems (EOLSS)
PHYTOCHEMISTRY AND PHARMACOGNOSY- The Origin of Pharmaceuticals - Eliezer J. Barreiro, Carlos Alberto M. Fraga and Lidia M. Lima Biographical Sketches Eliezer j. Barreiro (born in 1947) is Pharmacist (1971) and MSc. in Chemistry of Natural Products (1973) from Federal University of Rio de Janeiro (Brazil). He is Docteur-Иs-Sciences dґЙtat (1978) in Chimie Mйdicale from Universitй Scientifique et Mйdicale de Grenoble (France). Professor Barreiro is currently Full Professor of Medicinal Chemistry at Federal University of Rio de Janeiro since 1986. He published over 210 articles in specialized and indexed journals, including review articles (e.g. > 105 citations), has index h = 20 (Jan. 10, 2011). He is guest author of several chapters of books in Medicinal Chemistry, and author of 2 books in this field. He has 14 patent applications filed at INPI (BR) and a patent granted by the United States Patent and Trademark Office, number 7.091.238 of August 15, 2006. He is a mentor to more than 70 graduate students in the areas of Medicinal Chemistry, Pharmaceutical Chemistry, Pharmaceutical Sciences, Biochemistry and Pharmacology. He is scientific collaborator of over 350 scientists worldwide in joint research and scientific production. Prof. Barreiro received 7 scientific awards, including the Grand Master of the Order of National Scientific Merit of the Presidency of the Republic of Brazil (2010); the Order of National Scientific Merit of the Presidency of the Republic of Brazil (2004); the Rheinboldt-Hauptmann prize by the Institute of Chemistry of the University of Sгo Paulo, SP (27/11/2002). He is member of the Brazilian Academy of Sciences since 2001. He is also S fellow "Scientist of Rio de Janeiro State", FAPERJ. His research interests lie in the area of Medicinal Chemistry and Medicines or Pharmaceutical Chemistry. Currently, Prof. Barreiro is the scientific S S coordinator of the Laboratуrio de Avaliaзгo e Sнntese de Substвncias Bioativas (LASSBio,; i.e. Laboratory of Evaluation and Synthesis of Bioactive Substances) at L R Federal University of Rio de Janeiro (UFRJ; Brazil), which was founded in 1994. O E Carlos Alberto Manssour Fraga was born in Rio de Janeiro (Brazil) in 1964. He obtained a B.S. degree in Pharmacy in 1988 and his M.Sc. degree in Sciences (Medicinal Chemistry) from Federal University of E T Rio de Janeiro (UFRJ). After obtaining his PhD degrees from Chemistry Institute of UFRJ in 1994, working with the synthesis of novel stable prostacyclin mimetics under the supervision of Professor P Eliezer J. Barreiro, Carlos Alberto Manssour Fraga joined the Faculty of Pharmacy of UFRJ (Rio de ­ Janeiro) as Associate Professor in 1996 and was promoted to Professor in May 2006. He was Head of A Drug Department of Faculty of Pharmacy (UFRJ) from 2008 to 2010 and currently he is Coordinator of the Post Graduate Program in Pharmacology and Medicinal Chemistry of Institute of Biomedical O H Sciences of UFRJ. Dr. Fraga is effective member of Brazilian Chemical Society since 1991, where he was Director of Medicinal Chemistry Division from 2002 to 2004. Apart from teaching, Professor Fraga C C develop his research activities in LASSBio® (Laboratуrio de Avaliaзгo e Sнntese de Substвncias Bioativas, UFRJ), focusing the design, synthesis and pharmacological evaluation of novel drug candidates S able to act in multifactorial diseases, with particular emphasis in the use of N-acylhydrazone framework E as privileged structure to discovery novel therapeutically valuable compounds. E L Lidia M. Lima obtained her B.S. degree in Pharmacy from the Federal University of Rio de Janeiro N P (UFRJ, Brazil, 1994), MSc. in Organic Chemistry (UFRJ, BR, 1997), PhD in Medicinal Chemistry (UFRJ, BR, 2001) and a Post-Doctorate training in Medicinal Chemistry in the University of Navarra U (UNAV, Pamplona, Spain). She is currently an Associate Professor at the Pharmacy College in the M Federal University of Rio de Janeiro (UFRJ), teaching and supervising undergraduate and graduate students in the field of Medicinal Chemistry. Her research projects aim at contributing to the discovery of A new drugs of various therapeutic classes, such as anti-inflammatory, anti-asthmatic, anti-cancer, antiviral S and antiparasitic. She was granted a fellowship "Young Scientist of Rio de Janeiro State" (FAPERJ, BR) and a productivity grant from the National Council for Scientific and technological development (CNPq, BR). She is currently Secretary of the Brazilian Chemical Society Regional Rio de Janeiro (SBQ-Rio, 2010-2012). ©Encyclopedia of Life Support Systems (EOLSS)

EJ Barreiro

File: the-origin-of-pharmaceuticals.pdf
Author: EJ Barreiro
Author: Eliezer J. Barreiro
Subject: Phytochemistry and Pharmacognosy
Keywords: natural products; medicinal chemistry, lead-compound, drug-candidates
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