DOCSLIB.ORG

United States Patent (19) 11 Patent Number: 5,789,605 Smith, I Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
United States Patent (19) 11 Patent Number: 5,789,605 Smith, I Et Al IIIUSOO5789605A United States Patent (19) 11 Patent Number: 5,789,605 Smith, I et al. 45) Date of Patent: Aug. 4, 1998 54 SYNTHETICTECHNIQUES AND Jacquesy et al., "Metabromation Du Dimethyl-2, 6 Phenol INTERMEDIATES FOR POLYHYDROXY, Et De Son Ether Methylique En Milieu Superacide", Tetra DENYL LACTONES AND MIMCS hedron, 1981, 37, 747-751. THEREOF Kim et al., "Conversion of Acetals into Monothioacetals, O-Alkoxyazides and O-Alkoxyalkyl Thioacetates with 75) Inventors: Amos B. Smith, III. Merion; Yuping Magnesium Bromide". Tetra, lett, 1989, 30(48), Qiu; Michael Kaufman, both of 6697-6700. Philadelphia; Hirokaza Arimoto, Longley et al., "Discodermolide-A New, Marine-Derived Drexel Hill, all of Pa.; David R. Jones, Immunosuppressive Compound". Transplantation, 1991. Milford, Ohio; Kaoru Kobayashi, 52(4) 650-656. Osaka, Japan Longley et al., "Discodermolide-A New, Marine-Derived Immunosuppressive Compound". Transplantation, 1991. 73 Assignee: Trustees of the University of 52(4), 657-661. Pennsylvania, Philadelphia, Pa. Longley et al., "Immunosuppression by Discodermolide". Ann. N.Y. Acad. Sci., 1993. 696, 94-107. (21) Appl. No.:759,817 Nerenburg et al., "Total Synthesis of the Immunosuppres 22 Filed: Dec. 3, 1996 sive Agent (-)-Discodermolide". J. Am. Chem, Soc., 1993, 115, 12621-12622. (51) Int. Cl. ................. C07D407/06; C07D 319/06; Paterson, I. et al., "Studies Towards the Total Synthesis of CO7D 309/10 the Marine-derived Immunosuppressant Discodermolide; (52) U.S. Cl. .......................... 549/370; 549/374; 549/417 Asymmetric Synthesis of a C-Cö-Lactone Subunit". J. (58) Field of Search ..................................... 549/370,374, Chen. Soc. Chen, Commun., 1993, 1790-1792. 549/417 Paterson, I. et al., "Studies Towards the Total Synthesis of the Marine-derived Immunosuppresant Discodermolide; 56 References Cited Asymmetric Synthesis of a C-C Subunit". Synlett, 1995. Remington's Pharmaceutical Sciences, Mack Publishing FOREIGN PATENT DOCUMENTS Company. Easton, PA, 1980. 2280677 2/1995 United Kingdom. Roush et al., "Acyclic Diastereoselective Synthesis Using Tartrate Ester Modified Crotylboronates. Double Asymmet OTHER PUBLICATIONS ric Reactions with ol-Methyl Chiral Aldehydes and Synthe Clark. D.L. et al., "Studies on the Alkylation of Chiral sis of the C(19) -CO29) Segment of Rifamycin S". J. Am. Enolates: Application toward the Total Synthesis of Disco Chen. Soc., 1990, 112, 6348-6359. dermolide". J. Org. Chem, 1993. 58, 5878-5879. Smith et al., "Total Synthesis of (-)-Discodermolide", J. Evans. P.L. et al., "The Synthesis of a C-C Lactone Am. Chem. Soc., 1995, 117, 12011-12012. Fragment of Discodermolide". Tetra, Lett, 1993, 34(50), Smith, A. B. et al., "Total Synthesis of (-)-Discodermolide 8163-8166, Exploiting a Common Precursor". J. Am. Chem. Soc., (Sub Golec, J.M.C. et al., "The Synthesis of a C-CLactone mission Copy), 1-60. Fragment of Discodermolide", Tetra. Lett, 1993, 34 (50), 8159-8162. Solladie et al., "Asymmetric Synthesis of Polyhydroxylated Golec, J.M.C. et al., "An Approach to the Synthesis of a Natural Products II. The C-1/C-12 Unit of Amphotericin C-CFragment of Discodermolide", Tetra. Lett, 1993, B", Tetra. Lett, 1987, 28(7), 797-800. 34(50), 8167-8.168. ter Haar et al., “Discodermolide, A Cytotoxic Marine Agent Golec, J.M.C. et al., "Total synthesis of discodermolide", that Stabilizes Microtubules More Potently than Taxol", Chemical Abstracts, 1995, 123, 831, Abstract No. 32864j. Biochen., 1996, 35, 243-250. Greene and Wuts. Protective Groups in Organic Synthesis, Yang. G. et al., "the Synthsis of the C-9 to C-21 Sector of 2d Edition, John Wiley & Sons, New York, 1991. Discodermolide: An Efficient Route to the C13-14 Gunasekera et al., "Discodermolide: A New Bioactive Poly Z-Trisubstituted Alkene". Tetra. Lett, 1994, 35(16), hydroxylated Lactone from the Marine Sponge Discodernia 2503-2504. dissoluta”, J. Org. Chem, 1990. 55, 4912–4915. Yang. G. et al., "An Alkylative Strategy to the C-13 to C-21 Gunasekera et al., "Discodermolide: A New Bioactive Poly Sector of Discodermolide', Tetra. Lett, 1994, 35(9), hydroxylated Lactone from the Marine Sponge Discodermia 1313-1316. dissoluta. Additions and Corrections", J. Org. Chem, 1991, 56(3), 1346. Primary Examiner-Alan L. Rotman Hodges et al., "Reactions to Lithiooxazole”. J. Org. Chen, Assistant Examiner-Charanjit S. Aulakh 1991, 56, 449-452. Attorney, Agent, or Firm-Woodcock Washburn Kurtz Hung et al., "Distinct binding and cellular properties of Mackiewicz & Norris LLP synthetic (+)-and (-)-discodermolides". Chem, & Biol, 1994, 1(1), 67-71. 57 ABSTRACT Hung et al., "(+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks taxol binding Synthetic methods for lactone-containing compounds such and results in mitotic arrest", Chem. & Biol., 1996, 3(4), as the discodermolides are provided, as are compounds 287-293. which mimic the chemical and/or biological activity thereof, Hung, D.T. et al., "Syntheses of Discodermolides Useful for and methods and intermediates useful in their preparation. Investigating Microtubule Binding and Stabilization", J. Am. Chem. Soc., 1996, 118, 11054-11080. 9 Claims, 31 Drawing Sheets U.S. Patent Aug. 4, 1998 Sheet 1 of 31 5,789,605 Figure 1 ÖTBs PMP A(2) Common Precursor (5) Denote the repeating stereochemical triad Figure 2 NH l to-co. "EGO"1) PMBO1 CC, PPTS PMBO -- OH (-)-6 2) LiAlH, THF (74%, 2 steps) (-)-8 Bn 1) soSwern (O) Pouli O 2) "- 5- O 1. (+)-9 (+)-10 n-BuBOTf, EtN, CH2Cl2 (89%, 2 steps) HN(Me)OMeeHC AIMe, THF (89%) OH O Common Precursor (+)-5 U.S. Patent Aug. 4, 1998 Sheet 2 of 31 5,789,605 Figure 3 i: Me MeN s Pouls. DDC, CHCa YOMe iAlH. THF CHO ÖH 5 (76%) olo o (80%) on-o Common Precursor (+)-6 FMP (-)-11 FMP (-12 TBSO, 2,6-ut n-BuBOTT, EN CHC (100%) CHCl2 (80%) OH TsC, py Og LiBH, EtOH (100%) THF (81%) 6.6 ÖTes i (-)-15 PMP PhP, la, imid. N (95%)(1:2) O Fup Fragment (-)-A(2) U.S. Patent Aug. 4, 1998 Sheet 3 of 31 5,789,605 ewo) (%98) #eun61-I OHO,! salg ew OBWd(el=N'Rosw U.S. Patent Aug. 4, 1998 Sheet 4 of 31 5,789,605 Figure 5 a) -Buli (2 equiv) THF, -78 C; b) MgBr os-o OTBS c) PMBO Br PMP 1 N= (-)-A(2) (-)-22 OTBs PaCl2(dppf), EtO, RT (14%) Figure 6 PMBO ÖTBsis ----6TBs (22 DDQ (1.0 equiv) (-25 (83%) CH2Cl2, H2O OH (), d dTBs (-)-15 PMP (86% recovery) U.S. Patent Aug. 4, 1998 Sheet 5 of 31 5,789,605 ?WO QQSBL KOHO Ou8 U.S. Patent 5,789,605 (£)E-(-) U.S. Patent Aug. 4, 1998 Sheet 7 of 31 5,789,605 |?einfil salg w-(-) (pex?uJeug)?louz+ O d wd O~ U.S. Patent Aug. 4, 1998 Sheet 8 of 31 5,789,605 SELO U.S. Patent Aug. 4, 1998 Sheet 9 of 31 5,789,605 eleinfil Saigcs-(+) Oo08 (%96) U.S. Patent Aug. 4, 1998 Sheet 10 of 31 5,789,605 (%89) y!einfil U.S. Patent Aug. 4, 1998 Sheet 11 of 31 5,789,605 SB19 saloº saloº ”OSEL 09-(-) gawd saloº saloº (%56) U.S. Patent Aug. 4, 1998 Sheet 12 of 31 5,789,605 20] 91eun61-I 10! 3:0|| |91-8) U.S. Patent Aug. 4, 1998 Sheet 13 of 31 5,789,605 HO SELLO A01 NOBIA/-IH90,8; U.S. Patent Aug. 4, 1998 Sheet 14 of 31 5,789,605 U.S. Patent Aug. 4, 1998 Sheet 15 of 31 5,789,605 Salg U.S. Patent Aug. 4, 1998 Sheet 16 of 31 5,789,605 Ozein61-3 U.S. Patent Aug. 4, 1998 Sheet 17 of 31 5,789,605 U.S. Patent Aug. 4, 1998 Sheet 18 of 31 5,789,605 ZZ?un61-) OEWd U.S. Patent Aug. 4, 1998 Sheet 19 of 31 5,789,605 U.S. Patent Aug. 4, 1998 Sheet 20 of 31 5,789,605 Figure 24 BL EtO Eoul- Pd(PPh), 1) NaHMDS, THF --Orls-as-s- SO2 TBSOCHO 1 n TBSO OS c 1) DOC so C Xs OPMB B 2) PPha so4 - x = PPPh midazole SE OPMB 3) PPhi-Print EEO THF 2) DMSO, AcO 3) PPTS/MeOH EDC 501 U.S. Patent Aug. 4, 1998 Sheet 21 of 31 5,789,605 Figure 25 OTBS CHO 602 15 63 2) DiBAL CHCl2 1) TsC, Pyr. OPMBOTBS OTBS 1) PPTS/MeOH 2) Praculif Eto 2) MnO2 Phh OPMEOTBS OTBS 1) DDC / CHCHO 2) HF f MeCN U.S. Patent Aug. 4, 1998 Sheet 22 of 31 5,789,605 Figure 26 s DBAL-H -- El2 -- CH2Cl2 on-o OTBS Y O OTBS -raisera-e- PMB A PMB PPh s PPh. s PH 2 refix OH OPMBOTBS OPMBOTBS 703 : R Ph3P* I OPMBOTBs 2) t 705 O Q-lis 706 OPMBOTBS 707 80% ACOH OTs room temp. OPMBOTBS 709 K2CO3 MeOH DOC CH2C2-H2O OPMBOTBS OH OTBS CCCONCO (CICH2)2,MeOH K2CO HF / CHCN st-e-arreal-e- U.S. Patent Aug. 4, 1998 Sheet 23 of 31 5,789,605 Figure 27 OH OPMBOTBS PPh PPh 2 : Ph 16 inidazole R reflux TBSO OPMBOTBS O2 SEt 80% AcOH R room temp. PhP OPMBOTBS 2) t 803 du OPMBOTBS CHO 805 K2CO MeOH OPMBOTBS OPMBOBS 808 807 OPMBOBS SE U.S. Patent Aug. 4, 1998 Sheet 25 of 31 5,789,605 Figure 29 2) DiBAL, CHC 1) Sospyr, DMSO, EN 2 OTBS 1) PPTS/MeOH 2)glycosy bromide (Ooe) s: 3:) Hger CHC U.S. Patent Aug. 4, 1998 Sheet 26 of 31 5,789,605 'ULOSELL(£ [×] U.S. Patent Aug. 4, 1998 Sheet 27 of 31 5,789,605 U.S. Patent Aug. 4, 1998 Sheet 28 of 31 5,789,605 U.S.
Load more

Recommended publications
  • Download (1MB)
    THE IN VITRO METABOLISM OF THREE ANTICANCER DRUGS by Yun Fan B.S., West China University of Medical Sciences, 1996 M.S., West China University of Medical Sciences, 2001 Submitted to the Graduate Faculty of School of Pharmacy in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2007 UNIVERSITY OF PITTSBURGH SCHOOL OF PHARMACY This dissertation was presented by Yun Fan It was defended on March 23, 2007 and approved by Samuel M. Poloyac, Assistant Professor, Pharmaceutical Sciences Raman Venkataramanan, Professor, Pharmaceutical Sciences Jack C. Yalowich, Associate Professor, Pharmacology Michael A. Zemaitis, Professor, Pharmaceutical Sciences Billy W. Day, Professor, Pharmaceutical Sciences ii Copyright © by Yun Fan 2007 iii THE IN VITRO METABOLISM OF THREE ANTICANCER DRUGS Yun Fan, Ph.D. University of Pittsburgh, 2007 Etoposide is a widely used topoisomerase II inhibitor particularly useful in the clinic for treatment of disseminated tumors, including childhood leukemia. However, its use is associated with the increased risk of development of secondary acute myelogenous leukemias. The mechanism behind this is still unclear. It was hypothesized that etoposide ortho-quinone, a reactive metabolite previously shown to be generated in vitro by myeloperoxidase, the major oxidative enzyme in the bone marrow cells from which the secondary leukemias arise, might be a contributor to the development of treatment-related secondary leukemias. Experiments showed that the glutathione adduct of etoposide ortho-quinone was formed in myeloperoxidase- expressing human myeloid leukemia HL60 cells treated with etoposide, that its formation was enhanced by addition of the myeloperoxidase substrate hydrogen peroxide, and that the glutathione adduct level was dependent on myeloperoxidase.
    [Show full text]
  • Nicole Goodwin Macmillan Group Meeting April 21, 2004
    Discodermolide A Synthetic Challenge Me Me Me HO Me O O OH O NH2 Me Me OH O Me Me OH Nicole Goodwin MacMillan Group Meeting April 21, 2004 Me Me Me HO Discodermolide Me O O OH O NH2 Isolation and Biological Activity Me Me OH O Me Me OH ! Isolated in 1990 by the Harbor Branch Oceanographic Institution from the Caribbean deep-sea sponge Discodermia dissoluta ! Not practical to produce discodermolide from biological sources ! 0.002% (by mass) isolation from frozen sponge ! must be deep-sea harvested at a depth in excess of 33 m ! Causes cell-cycle arrest at the G2/M phase boundary and cell death by apoptosis ! Member of an elite group of natural products that act as microtubule-stabilizing agent and mitotic spindle poisons ! Taxol, epothilones A and B, sarcodictyin A, eleutherobin, laulimalide, FR182877, peloruside A, dictyostatin ! Effective in Taxol-resistant carcinoma cells ! presence of a small concentration of Taxol amplified discodermolide's toxicity by 20-fold ! potential synergies with the combination of discodermolide with Taxol and other anticancer drugs ! Licensed by Novartis from HBOI in 1998 as a new-generation anticancer drug 1 Cell Apoptosis M - Mitosis G0 Discodermolide disrupts the G2/M phases of the cell cycle. Resting Discodermolide, like Taxol, inhibits microtubule depolymerization by binding G1 - Gap 1 to tubulin. G2 - Gap 2 cells increase in size, cell growth control checkpoint no microtubules = no spindle fiber new proteins formation S - Synthesis DNA replication Me Me Me HO Discodermolide Me O O OH O NH2 Isolation
    [Show full text]
  • Dissertation.Pdf (1.198Mb)
    Syntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide Analogs Chao Yang Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University In the partial fulfillment of the requirement for the degree of Doctor of Philosophy In Chemistry Dr. David G. I. Kingston, Chairman Dr. Karen Brewer Dr. Paul R. Carlier Dr. Felicia. Etzkorn Dr. Harry W. Gibson August 26 2008 Blacksburg, Virginia Keywords: Taxol, drug targeting, , thio-taxol, tubulin-binding conformation, , T-taxol conformation, macrocyclic taxoids, discodermolide Copyright 2008, Chao Yang Syntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide Analogs Chao Yang Abstract Paclitaxel was isolated from the bark of Taxus brevifolia in the late 1960s. It exerts its biological effect by promoting tubulin polymerization and stabilizing the resulting microtubules. Paclitaxel has become one of the most important current drugs for the treatment of breast and ovarian cancers. Studies aimed at understanding the biologically active conformation of paclitaxel bound on β–tubulin are described. In this work, the synthesis of isotopically labeled taxol analogs is described and the REDOR studies of this compound complexed to tubulin agrees with the hypothesis that palictaxel adopts T-taxol conformation. Based on T-taxol conformation, macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. The results show a direct evidence to support T-taxol conformation. (+) Discodermolide is a polyketide isolated from the Caribbean deep sea sponge Discodermia dissoluta in 1990. Similar to paclitaxel, discodermolide interacts with tubulin and stabilizes the microtubule in vivo. Studies aimed at understanding the biologically active conformation of discodermolide bound on β–tubulin are described.
    [Show full text]
  • Total Synthesis of the Marine Natural Product (+)-Discodermolide in Multigram Quantities*
    Pure Appl. Chem., Vol. 79, No. 4, pp. 685–700, 2007. doi:10.1351/pac200779040685 © 2007 IUPAC Total synthesis of the marine natural product (+)-discodermolide in multigram quantities* Stuart J. Mickel Novartis Pharma AG, CHAD, WKL-684.2.31 Klybeckstrasse, 4052 Basel, Switzerland Abstract: The novel polyketide (+)-discodermolide was isolated in very small quantities from sponge extracts. This compound is one of several microtubule stabilizers showing promise as novel chemotherapeutic agents for the treatment of cancer. The clinical evaluation of this and similar compounds is hampered by lack of material, and at present, the only way to obtain the necessary quantities is total chemical synthesis. Keywords: discodermolide; boron aldol reaction; isolation; side products; olefination. INTRODUCTION The marine natural product (+)-discodermolide 1 was isolated by workers at the Harbor Branch Oceanographic Institute from the deep-sea sponge Discodermia dissoluta in 1990 [1]. It is obtained from the sponge in extremely small quantities, 0.002 % in the frozen material. This compound is one of several natural products exhibiting inhibition of microtubule depolymerization and as such shows considerable promise as a novel chemotherapeutic agent for the treatment of cancer [2]. In contrast to Taxol®, another microtubule stabilizer, (+)-1 shows activity in the Taxol-resistant cell lines which over- express P-glycoprotein, the multidrug-resistant transporter. The similarities and differences between (+)-1 and Taxol have recently been discussed in detail [3]. The structure of (+)-1 consists of a linear polypropionate chain interrupted by 3 cis-olefins. It con- tains 13 chiral centers, 6 of which are hydroxyl groups, one esterified as a lactone, another as a car- bamic acid ester.
    [Show full text]
  • Marine Natural Products: a Source of Novel Anticancer Drugs
    marine drugs Review Marine Natural Products: A Source of Novel Anticancer Drugs Shaden A. M. Khalifa 1,2, Nizar Elias 3, Mohamed A. Farag 4,5, Lei Chen 6, Aamer Saeed 7 , Mohamed-Elamir F. Hegazy 8,9, Moustafa S. Moustafa 10, Aida Abd El-Wahed 10, Saleh M. Al-Mousawi 10, Syed G. Musharraf 11, Fang-Rong Chang 12 , Arihiro Iwasaki 13 , Kiyotake Suenaga 13 , Muaaz Alajlani 14,15, Ulf Göransson 15 and Hesham R. El-Seedi 15,16,17,18,* 1 Clinical Research Centre, Karolinska University Hospital, Novum, 14157 Huddinge, Stockholm, Sweden 2 Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE 106 91 Stockholm, Sweden 3 Department of Laboratory Medicine, Faculty of Medicine, University of Kalamoon, P.O. Box 222 Dayr Atiyah, Syria 4 Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini St., P.B. 11562 Cairo, Egypt 5 Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, 11835 New Cairo, Egypt 6 College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China 7 Department of Chemitry, Quaid-i-Azam University, Islamabad 45320, Pakistan 8 Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany 9 Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, 12622 Giza, Egypt 10 Department of Chemistry, Faculty of Science, University of Kuwait, 13060 Safat, Kuwait 11 H.E.J. Research Institute of Chemistry,
    [Show full text]
  • Aldol Reactions: E-Enolates and Anti-Selectivity
    Utah State University DigitalCommons@USU All Graduate Plan B and other Reports Graduate Studies 5-2005 Aldol Reactions: E-Enolates and Anti-Selectivity Matthew Grant Anderson Utah State University Follow this and additional works at: https://digitalcommons.usu.edu/gradreports Part of the Organic Chemistry Commons Recommended Citation Anderson, Matthew Grant, "Aldol Reactions: E-Enolates and Anti-Selectivity" (2005). All Graduate Plan B and other Reports. 1312. https://digitalcommons.usu.edu/gradreports/1312 This Report is brought to you for free and open access by the Graduate Studies at DigitalCommons@USU. It has been accepted for inclusion in All Graduate Plan B and other Reports by an authorized administrator of DigitalCommons@USU. For more information, please contact [email protected]. ALDOL REACTIONS: E-ENOLATES AND ANTI-SELECTIVITY Prepared By: MATTHEW GRANT ANDERSON A non-thesis paper submitted in partial fulfillment of the requirement for a Plan B Degree of Masters of Science in Organic Chemistry UTAH STATE UNIVERSITY Logan, Utah 2005 Contents Page CONTENTS ...................................................................................... .i LIST OF TABLES, FIGURES AND SCHEMES ....................................... ii,iii ABSTRACT .................................................................................... iv CHAPTER I. ALDOL REACTIONS:E-ENOLATES AND ANTI SELECTIVITY ......... 1 CHAPTER II. SECTION 1. MODELS OF E-ENOLATE FORMATION ...... .... ....... ... 12 SECTION 2. PATERSON ENOLATE PAPER ..... .........................
    [Show full text]
  • (+)-Discodermolide: a Marine Natural Product Against Cancer
    Review Article TheScientificWorldJOURNAL (2004) 4, 415–436 ISSN 1537-744X; DOI 10.1100/tsw.2004.96 (+)-Discodermolide: A Marine Natural Product Against Cancer Marcus Vinícius Nora De Souza FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro-RJ E-mail: [email protected] Received February 25, 2004; Revised May 1, 2004; Accepted May 25, 2004; Published June 11, 2004 (+)-Discodermolide was isolated in 1990 by Gunasekera et al. from the deep-water Caribbean sponge Discodermia dissoluta. It attacks cancer cells in a similar way to the successful cancer drug Taxol® that has become the best-selling anticancer drug in history. Taxol is also the first natural product described that stabilizes the microtubules involved in many aspects of cellular biology and that represent an important target of anticancer chemotherapeutics. However, (+)-discodermolide appears to be far more potent than Taxol® against tumors that have developed multiple-drug resistance, with an IC50 in the low nanomolar range. Due to these excellent results, this natural product was licensed to Novartis Pharmaceutical Corporation in early 1998. The present review covers the history, biological activity, total synthesis, and synthetic analogs of (+)- discodermolide. KEYWORDS: (+)-discodermolide, cancer, tubuline, natural products DOMAINS: drug discovery INTRODUCTION Cancer is a growing public health problem with estimated worldwide new cases at over a million per year[1]. In the U.S., cancer is the second leading cause of death after heart disease, but it is the major cause of death in women between the ages of 35 and 74[2].
    [Show full text]
  • Current Screening Methodologies in Drug Discovery for Selected Human Diseases
    marine drugs Review Current Screening Methodologies in Drug Discovery for Selected Human Diseases Olga Maria Lage 1,2,*, María C. Ramos 3, Rita Calisto 1,2, Eduarda Almeida 1,2, Vitor Vasconcelos 1,2 ID and Francisca Vicente 3 1 Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/nº 4169-007 Porto, Portugal; [email protected] (R.C.); [email protected] (E.A.); [email protected] (V.V.) 2 CIIMAR/CIMAR–Centro Interdisciplinar de Investigação Marinha e Ambiental–Universidade do Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal 3 Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Parque Tecnológico de Ciencias de la Salud, 18016 Granada, Spain; [email protected] (M.C.R.); [email protected] (F.V.) * Correspondence: [email protected]; Tel.: +351-22-0402724; Fax.: +351-22-0402799 Received: 7 August 2018; Accepted: 11 August 2018; Published: 14 August 2018 Abstract: The increase of many deadly diseases like infections by multidrug-resistant bacteria implies re-inventing the wheel on drug discovery. A better comprehension of the metabolisms and regulation of diseases, the increase in knowledge based on the study of disease-born microorganisms’ genomes, the development of more representative disease models and improvement of techniques, technologies, and computation applied to biology are advances that will foster drug discovery in upcoming years. In this paper, several aspects of current methodologies for drug discovery of antibacterial and antifungals, anti-tropical diseases, antibiofilm and antiquorum sensing, anticancer and neuroprotectors are considered.
    [Show full text]
  • NMR Insights Into the Bioactive 3D Structure of Discodermolide and Dictyostatin**
    FULL PAPER DOI: 10.1002/chem.200800039 The Bound Conformation of Microtubule-Stabilizing Agents: NMR Insights into the Bioactive 3D Structure of Discodermolide and Dictyostatin** Angeles Canales,[a] Ruth Matesanz,[a] Nicola M. Gardner,[b] JosØ Manuel Andreu,[a] Ian Paterson,[b] J. Fernando Díaz,*[a] and Jesffls JimØnez-Barbero*[a] Abstract: A protocol based on a com- skeleton between the major conformer spect to the major conformer in solu- bination of NMR experimental data in water solution and that bound to as- tion, and still displays mobility even with molecular mechanics calculations sembled microtubules. For DCT, the when bound. The bound conformer of and docking procedures has been em- deduced bound geometry presents DCT resembles that of DDM and pro- ployed to determine the microtubule- some key conformation differences vides very similar contacts with the re- bound conformation of two microtu- around certain torsion angles, with re- ceptor. Competition experiments indi- bule-stabilizing agents, discodermolide cate that both molecules compete with (DDM) and dictyostatin (DCT). The the taxane-binding site. A model of the Keywords: anticancer agents · con- data indicate that tubulin in assembled binding mode of DDM and DCT to tu- formation analysis · microtubules · microtubules recognizes DDM through bulin is proposed. molecular modeling · a conformational selection process, molecular recognition with minor changes in the molecular Introduction essential components of the cytoskeleton, are involved in cell motility, intracellular
    [Show full text]
  • Exploring Free Energy Profiles of Enantioselective Organocatalytic
    molecules Article Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence Moritz Weiß and Martin Brehm * Institut für Chemie, Martin-Luther-Universität Halle-Wittenberg, von-Danckelmann-Platz 4, D-06120 Halle (Saale), Germany; [email protected] * Correspondence: [email protected] Academic Editor: Benedito José Costa Received: 13 October 2020; Accepted: 8 December 2020; Published: 11 December 2020 Abstract: We present a computational study on the enantioselectivity of organocatalytic proline-catalyzed aldol reactions between aldehydes in dimethylformamide (DMF). To explore the free energy surface of the reaction, we apply two-dimensional metadynamics on top of ab initio molecular dynamics (AIMD) simulations with explicit solvent description on the DFT level of theory. We avoid unwanted side reactions by utilizing our newly developed hybrid AIMD (HyAIMD) simulation scheme, which adds a simple force field to the AIMD simulation to prevent unwanted bond breaking and formation. Our condensed phase simulation results are able to nicely reproduce the experimental findings, including the main stereoisomer that is formed, and give a correct qualitative prediction of the change in syn : anti product ratio with different substituents. Furthermore, we give a microscopic explanation for the selectivity. We show that both the explicit description of the solvent and the inclusion of entropic effects are vital to a good outcome—metadynamics simulations in vacuum and static nudged elastic band (NEB) calculations yield significantly worse predictions when compared to the experiment. The approach described here can be applied to a plethora of other enantioselective or organocatalytic reactions, enabling us to tune the catalyst or determine the solvent with the highest stereoselectivity.
    [Show full text]
  • Sponge Cell Culture
    Sponge cell culture Klaske J. Schippers Sponge cell culture Klaske J. Schippers Thesis committee Promotors Submitted in fulfillment of the requirements for the degree of doctor Prof. dr. ir. R.H. Wijffels at Wageningen University Professor of Bioprocess Engineering by the authority of the Rector Magnificus Wageningen University Prof. dr. M.J. Kropff, in the presence of the Co-promotors Thesis Committee appointed by the Academic Board to be defended in public Prof. dr. S.A. Pomponi on Friday 15 February 2013 Professor of Marine Biotechnology, Wageningen University / Professor Harbor at 4 p.m. in the Aula. Branch Oceanographic Institute-Florida Atlantic University, USA Dr.ir. D.E. Martens Assistant professor, Bioprocess Engineering Wageningen University Other members Prof. dr. J. van der Oost, Wageningen University Dr. N.J. de Voogd, Museum Naturalis, Leiden Prof. dr. M.J. Uriz, Centro de Estudios Avanzados de Blanes, Spain Dr. ir. G.P. Pijlman, Wageningen University This research was conducted under the auspices of the Graduate School VLAG (Advances studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Table of contents Chapter 1 Introduction and thesis outline 7 Chapter 2 Cultivation of sponges, sponge cells and symbionts: 21 achievements and future prospects. Advances in Marine Biology 2012. 62: 273-337. Chapter 3 Cell cycle analysis of primary sponge cell cultures. 87 In Vitro Cellular & Developmental Biology – Animal 2011. 47:302-311. Chapter 4 Toward development of a sponge cell line: comparison 105 of cell proliferation in sponge cell and tissue cultures. Submitted for publication. Chapter 5 Methods for insertion and expression of heterologous 127 genes in sponge cells.
    [Show full text]
  • Total Synthesis of a Potent Hybrid of the Anticancer Natural Products Dictyostatin and Discodermolide. Chemical Communications, 38, 4628-4630
    FAU Institutional Repository http://purl.fcla.edu/fau/fauir This paper was submitted by the faculty of FAU’s Harbor Branch Oceanographic Institute. Notice: ©2008 Royal Society of Chemistry. This manuscript is an author version with the final publication available and may be cited as: Paterson, I., Naylor, G. J., & Wright, A. E. (2008). Total synthesis of a potent hybrid of the anticancer natural products dictyostatin and discodermolide. Chemical Communications, 38, 4628-4630. doi:10.1039/b811575c COMMUNICATION www.rsc.org/chemcomm | ChemComm Total synthesis of a potent hybrid of the anticancer natural products dictyostatin and discodermolidewz Ian Paterson,*a Guy J. Naylora and Amy E. Wrightb Received (in Cambridge, UK) 10th July 2008, Accepted 30th July 2008 First published as an Advance Article on the web 28th August 2008 DOI: 10.1039/b811575c A potent dictyostatin–discodermolide hybrid was designed and there appears to be minimal spatial correlation between the synthesised; it showed enhanced cell growth inhibitory activity d-lactone of discodermolide and the dienoate of dictyostatin. relative to discodermolide in four human cancer cell lines In addition, the AutoDock-derived model for tubulin binding including the Taxol-resistant NCI/ADR-Res cell line. indicates they both occupy the taxoid site and share similar interactions with the protein residues of the receptor. Discodermolide1 (1, Fig. 1) and dictyostatin2,3 (2) are marine With this information in hand and building on our previous sponge-derived antimitotic polyketides which exhibit potent synthetic work,6,7 we sought to rationally design an active growth inhibition against a wide range of human cancer cell hybrid of these two anticancer natural products.
    [Show full text]