DOCSLIB.ORG

The Chemistry of Nine-Membered Enediyne Natural Products

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Chemistry of Nine-Membered Enediyne Natural Products The Chemistry of Nine-Membered Enediyne Natural Products Zhang Wang MacMillan Group Meeting April 17, 2013 Natural Products Sharing a Unique Structure OH O O H H OH O Me O MeO Cl OH HO O Me Cl O Me O O O H OH OH NC H OH [O] OH R2 cyanosporaside A R sporolide A H 1 [O] R OH [O] O O Cl O Me R1 = H, R2 = Cl Cl MeO H OH or R1 = Cl, R2 = H OH O O HO O O Me O H H Me OH O H OH OH NC OH cyanosporaside B sporolide B Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2006, 8, 1021-1024. Buchanan, G. O.; Williams, P. G.; Feling R. H.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2005, 7, 2731-2734. Natural Products Sharing a Unique Structure OH O O H H OH O Me O MeO Cl OH HO O Me Cl O Me O O O H OH OH NC H OH OH cyanosporaside A R sporolide A OH O O + "magic" Cl + "HCl" O Me Cl OH MeO H OH O O HO O O Me O H H Me OH O H OH OH NC OH cyanosporaside B sporolide B Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2006, 8, 1021-1024. Buchanan, G. O.; Williams, P. G.; Feling R. H.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2005, 7, 2731-2734. Examples of Nine-Membered Enediynes O OH O HO O O O OH OH O O HO O O Me Me O O Cl OMe OMe OH MeHN OH neocarzinostatin chromophore N1999A2 OH O Cl NH MeO O H H OMe HO O OH HO O O Me H Me N maduropeptin H chromophore HO Me Examples of Nine-Membered Enediynes Me O Me H2N O MeO O MeO HO Cl OH O O OMe O HN O O HO Me N O Cl HN Me O HO OH Me OH O O O O O Me O NMe2 H O H OH O O Me NMe2 proposed kedarcidin chromophore C-1027 chromophore Two Types of Nine-Membered Enediynes Ar OH HO O HN O HO O Me Cl N OH Me O OH O O O O HO O H O H OH O O Me Cl OMe NMe2 proposed kedarcidin chromophore N1999A2 O [O] Bergman cyclization Myers cyclization Ten-Membered Enediyne Natural Products O HO MeSSS NHCOOMe Me O Me Me I O Me H COOH O S O OH O HN N O O H HO O OMe OH O OMe OMe Me O O HO EtHN MeO MeO OH O OH OH I dynemicin A calicheamicin !1 O HO MeSSS NHCOOMe Me N MeS Me H O HN OH O O O OH HO HO NH O O O i-PrHN O OH MeO shishijimicin A uncialamycin Bergman Cyclization D H o H 200 C D H D D H D D D D ! p-Benzyne diradical intermediate MeOH, 200 oC O + OH Me no H Cl H CCl4 heat Cl Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660-661. Bergman Cyclization ! Nicolaou's distance theory based on calculation and experiments Ring c…d distance Compound size A° stability c unknown, 9 2.84 CH2 should cyclize d 3.25 cyclize at 25 oC (CH2)2 10 3.61 stable at 25 oC (CH2)3 11 stable at 25 oC 4.12 o t1/2 = 30 s at 200 C Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866-4868. Bergman Cyclization ! Magnus-Snyder least motion/strain energy theory c...d distance relative rate of Bergman strain energy release ° cyclization at 124 oC after cyclization A kcal O TBSO c 3.391 650 6.0 (cyclohexanone adopts a d chair conformer in product) O TBSO 3.368 (oxime) 1 -1.5 Global strain energy of starting material and product should be considered for complex molecules Snyder, J. P. J. Am. Chem. Soc. 1989, 111, 7630-7632. Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 4986-4987. Bergman Cyclization D H o H 200 C D H D D H ! Nucleophiles can react with p-benzyne diradical, producing phenyl anion H LiX, HOAc DMSO, 37 oC X X !G = -80 to -100 kJ/mol can be treated as towards halides Perrin, C. L.; Rodgers, B. L.; O'Connor, J. M. J. Am. Chem. Soc. 2007, 129, 4795-4799. Bergman Cyclization ! Cyanosporasides from enediyne precursor H OH O HO O Me Cl Me O NC OH OH Bergman cyanosporaside A O cyclization OH in seawater HO O Me O Me HO O Me + O Me OH O NC OH NC Cl OH O pre-cyanosporaside HO O Me H Me O NC OH cyanosporaside B Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2006, 8, 1021-1024. Bergman Cyclization ! Bergman cyclization of calicheamicin O O HO HO S S NHCOOMe NHCOOMe Me S H S- O O Nu: Sugar Sugar O O HO HO NHCH2OOMe NHCH2OOMe S S O O Sugar Sugar Bergman Cyclization ! Bergman cyclization of dynemicin Me Me COOH COOH OH O HN OH OH HN O O OMe OMe OH O OH OH OH OH dynemicin A Me Me COOH COOH OH OH HN OH O HN HO HO OMe OMe Nu Nu: OH OH OH OH OH OH Bergman Cyclization ! Bergman cyclization of dynemicin Me Me COOH OH OH HN COOH HO OH OH HN HO OMe Nu OMe Nu OH OH OH OH OH OH Myers Cyclization O O O O O O Nu: O OH O Nu Ar O ArCOO Me Me O O O O OH OH MeHN MeHN OH OH O O O OH Nu ArCOO Me O O OH MeHN OH Myers, A. G. Tetrahedron Lett. 1987, 28, 4493-4496. DNA Cleavage with Diradical favors T, A rich sequences Naphthoate parallels DNA base pairs positively charged amino sugar interacts with phosphate O O O O OH O binds DNA minor groove O Me Me O O OMe OH MeHN OH neocarzinostatin chromophore DNA Cleavage with Diradical O O O O O O Nu: O OH P Nu O O H Thymine Ar ArCOO H O O Me O Me O O O O OH MeHN OH OH MeHN P OH P P downstream O O Thymine reactions O Thymine O2 O O DNA cleavage O O O P P Goldberg, I. H. Acc. Chem. Res. 1991, 24, 191-198. Enediyne Natural Products Are Polyketides O O O O Me OH COOH O OH O HN O OMe O Me Me O O OH O OH OMe OH MeHN OH neocarzinostatin chromophore dynemicin A cleaved Liang, Z.-X. Nat. Prod. Rep. 2010, 27, 499-528. Apoprotein of Nine-Membered Enediynes O OH O HO O O O OH OH O O HO O O Me Me O N1999A2 O Cl OMe OMe OH MeHN OH • Nine-membered enediynes isolated with neocarzinostatin chromophore apoproteins except N1999A2 • Apoproteins protect and transport enediynes • Apoproteins have about 110 amino acids • Structural features of apoproteins avoid: external nucleophile attack, electrophile activation of epoxides, H-abstraction of diradical intermediates neocarzinostatin Baker, J. R.; Woolfson, D. N.; Muskett, F. W.; Stoneman, R. G.; Urbaniak, M. D.; Caddick, S. ChemBioChem 2007, 8, 704-717. Neocarzinostatin Chromophore 1957 isolation of carzinostatin O 1965 isolation of neocarzinostatin O O 1972 Bergman cyclization O 1979 1:1 noncovalent complex of a protein and chromophore OH was identified O 1985 gross structure of neocarzinostatin chromophore was identified O Me Me 1987 ten-membered enediynes were found O O Myers cyclization proposed OMe OH MeHN 1988 relative and absolute stereochemistry of neocarzinostatin OH chromophore was determined neocarzinostatin chromophore 1996 the aglycon was synthesized 1998 neocarzinostatin chromophore synthesized Nan Ji, PhD thesis, Harvard University 2006. Maduropeptin Chromophore isolation condition product composition OH O Tris•HCl and MeOH R = OMe, Cl, OH Cl NH MeO without Cl-, and MeOH R = OMe, OH O H use EtOH instead of MeOH R = OEt H R HO O OH HO O O Me H Me N H DNA cleaving ability HO Me R = Cl > R = OMe enhanced ability in basic media no DNA scission upon adding thiol Schroeder, D. R.; Colson, K. L.; Klohr, S. E.; Zein, N.; Langley, D. R.; Lee, M. S.; Matson, J. A.; Doyle, T. W. J. Am. Chem. Soc. 1994, 116, 9351-9352. Maduropeptin Chromophore OH O O N Cl N Cl MeO MeO O O H H HO O HO O OH HO OH HO O O Me O O Me H H Me N Me N H H HO HO Me Me Schroeder, D. R.; Colson, K. L.; Klohr, S. E.; Zein, N.; Langley, D. R.; Lee, M. S.; Matson, J. A.; Doyle, T. W. J. Am. Chem. Soc. 1994, 116, 9351-9352. C-1027 Chromophore H N H2N O 2 O O O HO Cl EtOH HO Cl O H O O O OMe OMe O H O O O HN HN Me HO OH Me HO OH O O O O O O Me Me NMe NMe2 2 in apoprotein kH/kD = 3.8 Yoshida, K.-i.; Minami, Y.; Otani, T.; Tada, Y.; Hirama, M. Tetrohedron Lett. 1994, 35, 5253-5256. C-1027 Chromophore 3 R bond order: 1.21, 1.44 A° R1 bond order: 1.35, 1.41 A° R2 Yoshida, K.-i.; Minami, Y.; Otani, T.; Tada, Y.; Hirama, M.
Load more

Recommended publications
  • C-1027, a Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells
    Research Article C-1027, A Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells Terry A. Beerman,1 Loretta S. Gawron,1 Seulkih Shin,1 Ben Shen,2 and Mary M. McHugh1 1Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York;and 2Division of Pharmaceutical Sciences, University of Wisconsin National Cooperative Drug Discovery Group, and Department of Chemistry, University of Wisconsin, Madison, Wisconsin Abstract identified primarily from studies with neocarzinostatin (NCS), a The hypoxic nature of cells within solid tumors limits the holo-form drug, consisting of an apoprotein carrier and an active efficacy of anticancer therapies such as ionizing radiation and chromophore, and was assumed to be representative of all agents conventional radiomimetics because their mechanisms re- in this class (11). The NCS chromophore contains a bicyclic quire oxygen to induce lethal DNA breaks. For example, the enediyne that damages DNA via a Myers-Saito cycloaromatization conventional radiomimetic enediyne neocarzinostatin is 4- reaction, resulting in a 2,6-indacene diradical structure capable of fold less cytotoxic to cells maintained in low oxygen (hypoxic) hydrogen abstractions from deoxyribose (12, 13). Subsequent to compared with normoxic conditions. By contrast, the ene- generation of a sugar radical, reaction with oxygen quickly and diyne C-1027 was nearly 3-fold more cytotoxic to hypoxic than efficiently leads to formation of hydroxyl radicals that induce to normoxic cells. Like other radiomimetics, C-1027 induced DSBs/SSBs at a 1:5 ratio. The more recently discovered holo-form DNA breaks to a lesser extent in cell-free, or cellular hypoxic, enediyne C-1027 (Fig.
    [Show full text]
  • Enediynes, Enyneallenes, Their Reactions, and Beyond
    Advanced Review Enediynes, enyne-allenes, their reactions, and beyond Elfi Kraka∗ and Dieter Cremer Enediynes undergo a Bergman cyclization reaction to form the labile 1,4-didehy- drobenzene (p-benzyne) biradical. The energetics of this reaction and the related Schreiner–Pascal reaction as well as that of the Myers–Saito and Schmittel reac- tions of enyne-allenes are discussed on the basis of a variety of quantum chemical and available experimental results. The computational investigation of enediynes has been beneficial for both experimentalists and theoreticians because it has led to new synthetic challenges and new computational methodologies. The accurate description of biradicals has been one of the results of this mutual fertilization. Other results have been the computer-assisted drug design of new antitumor antibiotics based on the biological activity of natural enediynes, the investigation of hetero- and metallo-enediynes, the use of enediynes in chemical synthesis and C materials science, or an understanding of catalyzed enediyne reactions. " 2013 John Wiley & Sons, Ltd. How to cite this article: WIREs Comput Mol Sci 2013. doi: 10.1002/wcms.1174 INTRODUCTION symmetry-allowed pericyclic reactions, (ii) aromatic- ity as a driving force for chemical reactions, and (iii) review on the enediynes is necessarily an ac- the investigation of labile intermediates with biradical count of intense and successful interdisciplinary A character. The henceforth called Bergman cyclization interactions of very different fields in chemistry provided deeper insight into the electronic structure involving among others organic chemistry, matrix of biradical intermediates, the mechanism of organic isolation spectroscopy, quantum chemistry, biochem- reactions, and orbital symmetry rules.
    [Show full text]
  • Inotuzumab Ozogamicin Is an Investigational Agent and Has Not Been Approved for Marketing by Any Regulatory Agency at This Time
    Inotuzumab Ozogamicin is an investigational agent and has not been approved for marketing by any regulatory agency at this time. ABOUT INOTUZUMAB OZOGAMICIN Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen found on cancer cells in almost all B-ALL patients, linked to a cytotoxic agent.1,2 When inotuzumab ozogamicin binds to the CD22 antigen on B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.3 ABOUT ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) Acute lymphoblastic leukemia (ALL) in adults is an aggressive leukemia that can be fatal within a matter of months if left untreated.4 While many potential treatments have been studied, only a limited number of medicines for relapsed or refractory adults with ALL have been approved by the FDA and other regulatory authorities in the past decade. The current standard treatment is intensive, lengthy chemotherapy with the goal of halting the signs and symptoms of ALL (called hematologic remission) and patients becoming eligible for a stem cell transplant.4 UNMET NEEDS IN ADULT ALL Statistics & Patient Characteristics Statistics & Patient Characteristics • In 2017, it is estimated that 5,970 cases of ALL • Approximately half of U.S. adults who learn they will be diagnosed in the United States, with about have ALL this year will not respond to commonly 4 in 10 cases occurring in adults.5 used chemotherapy agents (e.g., be refractory) or will eventually see their disease return (e.g., relapse).5 • While significant strides have been made in treating children with ALL, the opposite is true for adults with • The outlook for adults with relapsed or refractory the disease.
    [Show full text]
  • WO 2018/064165 A2 (.Pdf)
    (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 WO 2018/064165 A2 05 April 2018 (05.04.2018) W !P O PCT (51) International Patent Classification: Published: A61K 35/74 (20 15.0 1) C12N 1/21 (2006 .01) — without international search report and to be republished (21) International Application Number: upon receipt of that report (Rule 48.2(g)) PCT/US2017/053717 — with sequence listing part of description (Rule 5.2(a)) (22) International Filing Date: 27 September 2017 (27.09.2017) (25) Filing Language: English (26) Publication Langi English (30) Priority Data: 62/400,372 27 September 2016 (27.09.2016) US 62/508,885 19 May 2017 (19.05.2017) US 62/557,566 12 September 2017 (12.09.2017) US (71) Applicant: BOARD OF REGENTS, THE UNIVERSI¬ TY OF TEXAS SYSTEM [US/US]; 210 West 7th St., Austin, TX 78701 (US). (72) Inventors: WARGO, Jennifer; 1814 Bissonnet St., Hous ton, TX 77005 (US). GOPALAKRISHNAN, Vanch- eswaran; 7900 Cambridge, Apt. 10-lb, Houston, TX 77054 (US). (74) Agent: BYRD, Marshall, P.; Parker Highlander PLLC, 1120 S. Capital Of Texas Highway, Bldg. One, Suite 200, Austin, TX 78746 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 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.
    [Show full text]
  • Antibody-Drug Conjugates of Calicheamicin Derivative: Gemtuzumab Ozogamicin and Inotuzumab Ozogamicin
    CCR FOCUS Antibody-Drug Conjugates of Calicheamicin Derivative: Gemtuzumab Ozogamicin and Inotuzumab Ozogamicin Alejandro D. Ricart Abstract Antibody-drug conjugates (ADC) are an attractive approach for the treatment of acute myeloid leukemia and non-Hodgkin lymphomas, which in most cases, are inherently sensitive to cytotoxic agents. CD33 and CD22 are specific markers of myeloid leukemias and B-cell malignancies, respectively. These endocytic receptors are ideal for an ADC strategy because they can effectively carry the cytotoxic payload into the cell. Gemtuzumab ozogamicin (GO, Mylotarg) and inotuzumab ozogamicin consist of a derivative of calichea- micin (a potent DNA-binding cytotoxic antibiotic) linked to a humanized monoclonal IgG4 antibody directed against CD33 or CD22, respectively. Both of these ADCs have a target-mediated pharmacokinetic disposition. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed acute myeloid leukemia. In contrast, in phase III studies, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma, and it has started phase III evaluation. The safety profile of these ADCs includes reversible myelosuppression (especially neutropenia and thrombocyto- penia), elevated hepatic transaminases, and hyperbilirubinemia. There have been postmarketing reports of hepatotoxicity, especially veno-occlusive disease, associated with GO. The incidence is 2%, but patients who undergo hematopoietic stem cell transplantation have an increased risk. As we steadily move toward the goal of personalized medicine, these kinds of agents will provide a unique opportunity to treat selected patient subpopulations based on the expression of their specific tumor targets.
    [Show full text]
  • Design, Synthesis and Reactivity of Cyclopropenone
    DESIGN, SYNTHESIS AND REACTIVITY OF CYCLOPROPENONE- CONTAINING NINE MEMBERED CYCLIC ENEDIYNE AND ENYNE-ALLENE PRECURSORS AS PROTOTYPE PHOTOSWITCHABLE ANTITUMOR AGENTS by DINESH R. PANDITHAVIDANA (Under the Direction of Vladimir V. Popik) ABSTRACT The extreme cytotoxicity of natural enediyne antibiotics is attributed to the ability of the ( Z)-3-hexene-1,5-diyne (enediyne) and ( Z)-1,2,4-heptatrien-6-yne (enyne–allene) fragments incorporated into a 10- or 9-membered ring cyclic system to undergo cycloaromatization producing dDNA-damaging 1,4-diradicals. The rate of cyclization of enediynes to p-benzynes strongly depends on the distance between acetylenic termini, which in turn can be controlled by the ring size. Thus, 11-membered ring enediynes are stable, 10-membered ring analogs undergo slow cycloaromatization under ambient conditions or mild heating, 9- membered ring enediynes are virtually unknown and believed to undergo very fast spontaneous cyclization. Cyclic enyne-allenes have not been synthesized so far due to very facile Myers-Saito cyclization. We have developed thermally stable photo-precursors of 9-membered enediynes ( 2.22 , 2.26 ) and enyne-allene ( 2.44 ), in which one of the triple bonds is replaced by the cyclopropenone group. UV irradiation of 2.14 results in the efficient decarbonylation (Φ 254 = 0.34) and the formation of reactive enediyne 2.22. The latter undergoes clean cycloaromatization to 2,3-dihydro-1H- cyclopenta[b]naphthalen-1-ol ( 2.24 ) with a life-time of ca. 2 h in 2-propanol at 25 °C. The rate of this reaction depends linearly on the concentration of hydrogen donor and shows a primary kinetic isotope effect in 2-propanol-d8.
    [Show full text]
  • Molecular Biosystems
    Molecular BioSystems View Article Online PAPER View Journal | View Issue Cloning and sequencing of the kedarcidin biosynthetic Cite this: Mol. BioSyst., 2013, gene cluster from Streptoalloteichus sp. ATCC 53650 9, 478 revealing new insights into biosynthesis of the enediyne family of antitumor antibiotics† Jeremy R. Lohman,a Sheng-Xiong Huang,a Geoffrey P. Horsman,b Paul E. Dilfer,a Tingting Huang,a Yihua Chen,b Evelyn Wendt-Pienkowskib and Ben Shenz*abcd Enediyne natural product biosynthesis is characterized by a convergence of multiple pathways, generating unique peripheral moieties that are appended onto the distinctive enediyne core. Kedarcidin (KED) possesses two unique peripheral moieties, a (R)-2-aza-3-chloro-b-tyrosine and an iso- propoxy-bearing 2-naphthonate moiety, as well as two deoxysugars. The appendage pattern of these peripheral moieties to the enediyne core in KED differs from the other enediynes studied to date with respect to stereochemical configuration. To investigate the biosynthesis of these moieties and expand our understanding of enediyne core formation, the biosynthetic gene cluster for KED was cloned from Streptoalloteichus sp. ATCC 53650 and sequenced. Bioinformatics analysis of the ked cluster revealed the presence of the conserved genes encoding for enediyne core biosynthesis, type I and type II polyketide synthase loci likely responsible for 2-aza-L-tyrosine and 3,6,8-trihydroxy-2-naphthonate Received 16th November 2012, formation, and enzymes known for deoxysugar biosynthesis. Genes homologous to those responsible Accepted 20th January 2013 for the biosynthesis, activation, and coupling of the L-tyrosine-derived moieties from C-1027 and DOI: 10.1039/c3mb25523a maduropeptin and of the naphthonate moiety from neocarzinostatin are present in the ked cluster, supporting 2-aza-L-tyrosine and 3,6,8-trihydroxy-2-naphthoic acid as precursors, respectively, for the www.rsc.org/molecularbiosystems (R)-2-aza-3-chloro-b-tyrosine and the 2-naphthonate moieties in KED biosynthesis.
    [Show full text]
  • Probing Interaction Motifs for Ligand Binding Prediction from Three
    PROBING INTERACTION MOTIFS FOR LIGAND BINDING PREDICTION FROM THREE PERSPECTIVES: ASSESSING PROTEIN SIMILARITY, LIGAND SIMILARITY AND COMPONENTS OF PROTEIN-LIGAND INTERACTIONS By Nan Liu A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2015 ABSTRACT PROBING INTERACTION MOTIFS FOR LIGAND BINDING PREDICTION FROM THREE PERSPECTIVES: ASSESSING PROTEIN SIMILARITY, LIGAND SIMILARITY AND COMPONENTS OF PROTEIN-LIGAND INTERACTIONS By Nan Liu The interactions between small molecules and diverse enzyme, membrane receptor and channel proteins are associated with important biological processes and diseases. This makes the study of binding motifs between proteins and ligands appealing to scientists. We use multiple computational techniques to unveil the protein-ligand interaction motifs from three perspectives. Firstly, from the perspective of proteins, by comparing the structure differences and common features of different binding sites for the same ligand, 3-dimensional motifs that represent the favorable interactions of the same ligands can be extracted. The goal is for such a motif to represent the shared features for binding a certain ligand in unrelated proteins, while discriminating from other ligands. The 3-dimensional motifs for cholesterol and cholate binding to non-homologous protein sites have been extracted, using SimSite3D alignment and analysis of the conserved interactions between these sites. The 3-dimensional protein motif for cholesterol binding can give about 80% accuracy of true positive sites with a low false positive rate. Furthermore, an online server CholMine was established so that the users can use this approach to predict cholesterol and cholate binding sites in proteins of interest.
    [Show full text]
  • The Novel Calicheamicin-Conjugated CD22 Antibody Inotuzumab Ozogamicin (CMC-544) Effectively Kills Primary Pediatric Acute Lymphoblastic Leukemia Cells
    Leukemia (2012) 26, 255–264 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu ORIGINAL ARTICLE The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells JF de Vries1, CM Zwaan2, M De Bie1, JSA Voerman1, ML den Boer2, JJM van Dongen1 and VHJ van der Velden1 1Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands and 2Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands We investigated whether the newly developed antibody (Ab) - One of these new approaches is antibody (Ab)-targeted targeted therapy inotuzumab ozogamicin (CMC-544), consisting chemotherapy, where the Ab-part of the compound is used to of a humanized CD22 Ab linked to calicheamicin, is effective in specifically deliver the cytostatic drug to the target cell, resulting pediatric primary B-cell precursor acute lymphoblastic leuke- mia (BCP-ALL) cells in vitro, and analyzed which parameters in less or no bystander cell death. One of the first examples of Ab- determine its efficacy. CMC-544 induced dose-dependent cell based delivery is gemtuzumab ozogamicin (GO, Mylotarg kill in the majority of BCP-ALL cells, although IC50 values varied or CMA-676), which consists of a humanized CD33 Ab substantially (median 4.8 ng/ml, range 0.1–1000 ng/ml at 48 h). covalently linked to a derivative of the potent DNA-damaging The efficacy of CMC-544 was highly dependent on calicheami- cytotoxic agent calicheamicin.7,8 Calicheamicin induces cell cin sensitivity and CD22/CMC-544 internalization capacity of BCP-ALL cells, but hardly on basal and renewed CD22 death in its target cells by interaction with double-helical DNA in expression.
    [Show full text]
  • Isolation and Identification of Cyclic Polyketides From
    ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS Mohamad Nurul Azmi Mohamad Taib, Yvan Six, Marc Litaudon, Khalijah Awang To cite this version: Mohamad Nurul Azmi Mohamad Taib, Yvan Six, Marc Litaudon, Khalijah Awang. ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS . Chemical Sciences. Ecole Doctorale Polytechnique; Laboratoires de Synthase Organique (LSO), 2015. English. tel-01260359 HAL Id: tel-01260359 https://pastel.archives-ouvertes.fr/tel-01260359 Submitted on 22 Jan 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS MOHAMAD NURUL AZMI BIN MOHAMAD TAIB FACULTY OF SCIENCE UNIVERSITY
    [Show full text]
  • Selective Proteolytic Activity of the Antitumor Agent Kedarcidin N
    Proc. Natl. Acad. Sci. USA Vol. 90, pp. 8009-8012, September 1993 Biochemistry Selective proteolytic activity of the antitumor agent kedarcidin N. ZEIN*t, A. M. CASAZZA*, T. W. DOYLE*, J. E. LEETt, D. R. SCHROEDERt, W. SOLOMON*, AND S. G. NADLER§ *Cancer Drug Discovery, Molecular Drug Mechanism, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000; tChemistry Division, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5100, Wallingford, CT 06492-7660; and §Antitumor Immunology, Bristol-Myers Squibb Pharmaceutical Research Institute, 3005 1st Avenue, Seattle, WA 98121 Communicated by William P. Jencks, May 27, 1993 ABSTRACT Kedarcidin is a potent antitumor antibiotic there is substantial in vitro chemical and structural informa- chromoprotein, composed of an enediyne-containing chro- tion (4-21). Furthermore, it was proposed that the neocarzi- mophore embedded in a highly acidic single chain polypeptide. nostatin apoprotein stabilizes and regulates the availability of The chromophore was shown to cleave duplex DNA site- the labile chromophore (4-9). As previously shown for specifically in a single-stranded manner. Herein, we report that neocarzinostatin (4-9), DNA experiments with the isolated in vitro, the kedarcidin apoprotein, which lacks any detectable chromophore and the kedarcidin chromoprotein demon- chromophore, cleaves proteins selectively. Histones that are the strated that DNA cleavage was mostly due to the chro- most opposite in net charge to the apoprotein are cleaved most mophore (N.Z. and W.S., unpublished data). However, readily. Our findings imply that the potency of kedarcidin cytotoxicity assays using human colon cancer cell lines HCT results from the combination of a DNA damaging-chro- 116 showed the chromophore and the chromoprotein to mophore and a protease-like apoprotein.
    [Show full text]
  • Total Synthesis of Calicheamicin Type Enediyne Natural Products
    Total Synthesis of Calicheamicin Type Enediyne Natural Products 17/09/02 Yuki Fujimoto 1 Contents 2 Enediyne Natural Products SSS Me O OMe NHCO 2Me MeO O O H OH HO O N O O O OMe S O OH HO I OH O OMe O NHEt I calicheamicin 1 (calicheamicin type) OMe O O O O CO 2H OH O HN O O OMe OH O O MeH N HO OH O OH O OH dynemicin A (dynemicin type) neocarzinostatin chromophore (chromoprotein type) 3 Bergman Cyclization Jones, R. R.; Bergman, R. G . J. Am. Chem. Soc. 1972 , 94 , 660. 4 Distance of Diyne a) Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988 , 110 , 4866. 5 b) Nicolaou, K. C.; Dai, W. M. Angew. Chem. Int. Ed. Engl. 1991 , 30 , 1387. Calicheamicin Type Action Mechanism Nicolaou, K. C.; Dai, W. M. Angew. Chem. Int. Ed. Engl. 1991 , 30 , 1387 6 Contents 7 Introduction of Calicheamicin SSS Me O OMe NHCO 2Me MeO O O H OH HO O N O O O OMe S O OH HO I OH O OMe NHEt I O calicheamicin 1 SSS Me Isolation O 1) NHCO 2Me bacterial strain Micromonospora echinospora ssp calichensis I Total synthesis of calicheamicin 1 HO OH Nicolaou, K. C. (1992, enantiomeric) 2) Danishefsky (1994, enantiomeric) 3) Total synthesis of calicheamicinone Danishefsky, S. J. (1990, racemic) 4) Nicolaou, K. C. (1993, enantiomeric) 5) calicheamicinone Clive, D. L. J. (1996, racemic) 6) (calicheamicin aglycon) Magnus, P. (1998, racemic) 7) 1) Borders, D.
    [Show full text]