DOCSLIB.ORG

(12) STANDARD PATENT (11) Application No. AU 2015212733 B2 (19) AUSTRALIAN PATENT OFFICE

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) STANDARD PATENT (11) Application No. AU 2015212733 B2 (19) AUSTRALIAN PATENT OFFICE (12) STANDARD PATENT (11) Application No. AU 2015212733 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Small molecule drug conjugates (51) International Patent Classification(s) A61P 35/00 (2006.01) (21) Application No: 2015212733 (22) Date of Filing: 2015.02.03 (87) WIPO No: WO15/114171 (30) Priority Data (31) Number (32) Date (33) Country 1401819.6 2014.02.03 GB 1419994.7 2014.11.10 GB 1407530.3 2014.04.29 GB (43) Publication Date: 2015.08.06 (44) Accepted Journal Date: 2018.06.07 (71) Applicant(s) Eidgenoessische Technische Hochschule Zurich (72) Inventor(s) Krall, Nikolaus;Decurtins, Willy;Neri, Dario;Scheuermann, Jorg;Wichert, Moreno (74) Agent / Attorney Davies Collison Cave Pty Ltd, Level 10 301 Coronation Drive, MILTON, QLD, 4064, AU (56) Related Art NIKOLAUS KRALL ET AL, "Small Targeted Cytotoxics: Current State and Promises from DNA-Encoded Chemical Libraries", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, (2013-01-28), vol. 52, no. 5, doi:10.1002/ anie.201204631, pages 1384 - 1402 WO 2013167994 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2015/114171 Al 6 August 2015 (06.08.2015) W I PO I P CT (51) International Patent Classification: (81) Designated States (unless otherwise indicated,for every A61K 47/48 (2006.01) A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/EP2015/052214 DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 3 February 2015 (03.02.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 1401819.6 3 February 2014 (03.02.2014) GB (84) Designated States (unless otherwise indicated,for every 1407530.3 29 April 2014 (29.04.2014) GB kind of regional protection available): ARIPO (BW, GH, 1419994.7 10 November 2014 (10.11.2014) GB GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: EIDGENOESSISCHE TECHNISCHE TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, HOCHSCHULE ZURICH [CH/CH]; Wolfgang-Pauli- DK, EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Str.10, CH-8093 Zurich (CH). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: KRALL, Nikolaus; Ziehrerplatz 2/20, A-1030 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Wien (AT). DECURTINS, Willy; Feldeggweg 6, CH- GW, KM, ML, MR, NE, SN, TD, TG). 8810 Horgen (CH). NERI, Dario; Ziehlstrasse 35, CH- Published: 8107 Buchs (CH). SCHEUERMANN, Jirg; Quellenweg with internationalsearch report (Art. 21(3)) 5, CH-5436 Wfrenlos (CH). WICHERT, Moreno; Och senbodenweg 11, CH-8855 Wangen-Nuolen (CH). (74) Agent: MASCHIO, Antonio; Maschio & Soames IP Lim ited, 20 Carlton Crescent, Southampton Hampshire SOl5 2ET (GB). (54) Title: SMALL MOLECULE DRUG CONJUGATES (57) Abstract: A targeted therapeutic agent comprising a compound of formula (I): B-L-D, wherein: B is a low molecular weight binding moiety for Carbonic Anhydrase IX (CAIX); D is a drug moiety; and L is a linker group that undergoes cleavage in vivo for f4 releasing said drug moiety in an active form. The drug moiety is suitably a cytotoxic agent for targeted delivery to cancer cells ex pressing CAIX. The binding moiety B suitably comprises a sulfonamidothiadiazole moiety. The binding moiety B may comprise one, two or more groups capable of binding to CAIX. The linker group suitably comprises a disulfide bond and/or a triazole group and/or a cleavable peptide group. WO 2015/114171 PCT/EP2015/052214 1 SMALL MOLECULE DRUG CONJUGATES FIELD OF THE INVENTION 5 The present invention relates to the field of small molecule targeted drug conjugates (SMDCs) for the treatment of disease. In particular, the invention relates to SMDCs formed of a low molecular weight ligand for binding to Carbonic Anhydrase IX (CAIX), conjugated to a drug by a cleavable linker for delivery of the drug to targeted tissues or 10 cells. In one embodiment, the present invention relates to the application of such SMDCs for the delivery of drugs that can kill or inhibit tumour cells. BACKGROUND 15 The use of cytotoxic agents is at the basis of the treatment of cancer and other pathological conditions. Ideally cytotoxic agents should accumulate at site of disease, sparing normal tissues. In reality this does not happen. Many anticancer drugs do not preferentially accumulate in solid tumors. Indeed, it has been demonstrated in tumor-bearing mice that only a minimal portion of the injected drug reaches the neoplastic mass in comparison to 20 the amount of cytotoxic agent that reaches healthy organs. The targeted delivery of highly potent cytotoxic agents into diseased tissues is therefore desirable for the treatment of cancer and other serious conditions. By attaching a therapeutic effector through a cleavable linker to a ligand specific to a marker of disease, 25 the effector preferentially accumulates and acts at the intended site of action, thus increasing the effectively applied dose while reducing side effects. To date, monoclonal antibodies have been considered as the ligands of choice and, indeed, research in the field of antibody-drug conjugates (ADCs) has led to the recent approval of two ADCs for applications in oncology: brentuximab vedotin and trastuzumab emtansine. 30 However, antibodies are large macromolecules and thus often have difficulties penetrating deeply into solid tumors. In addition, they can be immunogenic and typically long circulation times can lead to premature drug release and undesired side effects. Moreover, WO 2015/114171 PCT/EP2015/052214 2 the production of ADCs is expensive, reflecting the need for clinical-grade manufacturing of antibodies, drugs and the resulting conjugates. The use of smaller ligands as delivery vehicles such as peptides or small drug-like 5 molecules could potentially overcome some of the abovementioned problems. Their reduced size should aid tissue penetration, they should be non-immunogenic and amenable to classic organic synthesis thus reducing manufacturing costs. The favorable properties of drug conjugates using folic acid or ligands against prostate-specific membrane antigen (PSMA) as delivery vehicles have been demonstrated and a folate conjugate has recently 10 entered Phase III clinical studies. However, only a few such conjugates have been successfully identified. W02006137092 describes the use of fluorophore-labeled Carbonic Anhydrase IX inhibitors for the treatment of cancers by inhibiting the activity of CAIX and thereby reversing 15 acidification of the extracellular environment of the tumour. There is no suggestion to use the CAIX inhibitors for targeting cytotoxic agents. Further CAIX inhibitors for the treatment of cancer are described in W02011098610 and W02004048544. The present inventors have found small molecule drug conjugates that target Carbonic Anhydrase IX (CAIX) expressing tumors. 20 SUMMARY OF THE INVENTION According to the first aspect of the invention, therefore, there is provided a targeted therapeutic agent comprising a compound of formula: 25 B-L-D (I), wherein: B is a low molecular weight binding moiety for a Carbonic Anhydrase; D is a drug moiety; and L is a linker group that undergoes cleavage in vivo for releasing said drug moiety in an 30 active form. The binding moiety B suitably binds to a tumor-associated carbonic anhydrase enzyme, most preferably it binds to Carbonic Anhydrase IX (CAIX). The binding to the carbonic WO 2015/114171 PCT/EP2015/052214 3 anhydrase is suitably selective or specific, whereby the binding moiety B accumulates in vivo at sites, such as tumors, where carbonic anhydrase is present at elevated levels. Alternatively or additionally, the binding moiety may bind to other carbonic anhydrases such as Carbonic Anhydrase XII. 5 Suitably, the compound of Formula (I) has a molecular weight less than about 8,000, more suitably less than about 5000, and most suitably less than about 2000. In contrast to antibodies, small molecules can diffuse out of blood vessels in a matter of seconds. The distribution is not restricted to perivascular space, but involves also deep penetration into 10 tissues. This results in faster, deeper and more efficient drug targeting by the agents of the invention. In another aspect, the present invention provides a targeted therapeutic agent in accordance with the first aspect of the invention, for use in the treatment of a neoplastic disease, 15 preferably for the treatment of a solid tumor, more preferably for the treatment of renal cell carcinoma. In another aspect, the present invention provides a pharmaceutical composition comprising a targeted therapeutic agent according to the first aspect of the invention. 20 In another aspect, the present invention provides a product comprising a compound of Formula (I) as defined herein and a cleavage agent for cleaving said cleavable linker L, as a combined preparation for sequential administration in the treatment of cancer. 25 In another aspect, the present invention provides a method of treating a neoplastic disease, preferably a solid tumor such as renal cell carcinoma, comprising administering an effective amount of a pharmaceutical composition according to the present invention to a patient in need thereof.
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]
  • 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".
    [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]