Molecular Determinants of Tissue Selectivity in Estrogen Receptor Modulators

Total Page:16

File Type:pdf, Size:1020Kb

Molecular Determinants of Tissue Selectivity in Estrogen Receptor Modulators Proc. Natl. Acad. Sci. USA Vol. 94, pp. 14105–14110, December 1997 Pharmacology Molecular determinants of tissue selectivity in estrogen receptor modulators TIMOTHY A. GRESE*, JAMES P. SLUKA*, HENRY U. BRYANT,GEORGE J. CULLINAN,ANDREW L. GLASEBROOK, CHARLES D. JONES,KEN MATSUMOTO,ALAN D. PALKOWITZ,MASAHIKO SATO,JOHN D. TERMINE, MARK A. WINTER,NA N. YANG, AND JEFFREY A. DODGE* Endocrine Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 Edited by Paul Talalay, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 3, 1997 (received for review July 3, 1997) ABSTRACT Interaction of the estrogen receptoryligand molecular conformation of individual ligands (11–14). The complex with a DNA estrogen response element is known to recent characterization of a new ER isoform, ERb, adds a regulate gene transcription. In turn, specific conformations of further layer of complexity, because ligands with different the receptor-ligand complex have been postulated to influence structural characteristics may exhibit different binding profiles unique subsets of estrogen-responsive genes resulting in differ- depending on which ER isoform is being evaluated (15, 16). ential modulation and, ultimately, tissue-selective outcomes. The To date, ER ligands have been grouped into four classes on the estrogen receptor ligands raloxifene and tamoxifen have dem- basis of in vivo pharmacology, and representatives of these classes onstrated such tissue-specific estrogen agonistyantagonist ef- indeed have been shown to exhibit unique profiles with respect to fects. Both agents antagonize the effects of estrogen on mammary transcriptional activation (9). Differential effects on mammary, tissue while mimicking the actions of estrogen on bone. However, uterine, cardiovascular, and skeletal tissues have been observed tamoxifen induces significant stimulation of uterine tissue for each of the four classes (17). At opposing ends of the whereas raloxifene does not. We postulate that structural dif- pharmacological spectrum are 17b-estradiol and ICI-164,384; the ferences between raloxifene and tamoxifen may influence the former is the natural ligand and a full agonist in target tissues conformations of their respective receptoryligand complexes, whereas the latter appears to be essentially a pure antagonist in thereby affecting which estrogen-responsive genes are modulated vivo (17, 18). In between these two extremes lie other ER ligands in various tissues. These structural differences are 4-fold: (A) the such as tamoxifen and raloxifene (Fig. 1), which exert tissue- presence of phenolic hydroxyls, (B) different substituents on the selective estrogen-like effects. Both act as estrogen antagonists in basic amine, (C) incorporation of the stilbene moiety into a cyclic mammary tissue, but mimic the agonist effects of estrogen on benzothiophene framework, and (D) the imposition of a carbonyl bone and in the cardiovascular system (19). In the uterus, ‘‘hinge’’ between the basic amine-containing side chain and the however, tamoxifen induces significant stimulation and appears olefin. A series of raloxifene analogs that separately exemplify to function as a partial estrogen agonist, whereas raloxifene each of these differences have been prepared and evaluated in a appears to function entirely as an antagonist. This uterine agonist series of in vitro and in vivo assays. This strategy has resulted in activity has been associated with an increased risk of endometrial the development of a pharmacophore model that attributes the cancer for patients treated with tamoxifen (20). Because of its differences in effects on the uterus between raloxifene and unique profile of tissue specificity, raloxifene has been charac- tamoxifen to a low-energy conformational preference imparting terized as a selective estrogen receptor modulator and is presently an orthogonal orientation of the basic side chain with respect to in clinical development for the prevention and treatment of the stilbene plane. This three-dimensional array is dictated by a postmenopausal osteoporosis (21, 22). Recently, a potential single carbon atom in the hinge region of raloxifene. These data mechanism for this tissue specificity involving selective interac- indicate that differences in tissue selective actions among ben- tion of the ER-raloxifene complex with a response element zothiophene and triarylethylene estrogen receptor modulators distinct from the classical estrogen response element has been can be ascribed to discrete ligand conformations. proposed (8). As part of our program to explore the pharmacol- ogy of raloxifene and related molecules, we have sought to Recent advances in understanding the mechanisms by which uncover the molecular features that account for its unique profile nuclear hormone receptors exert their effects on gene tran- of tissue specificity, particularly those features that differentiate scription have greatly enhanced the prospects for tissue- it from tamoxifen. Four major structural differences are apparent selective regulation of these processes (1–4). The recognition on inspection (Fig. 1): (A) the presence of the phenolic hydroxyls, that the estrogen receptor (ER) may interact with more than (B) the nature of the basic amine, (C) the incorporation of the one DNA response element, that these interactions may be stilbene into a cyclic benzothiophene framework, and (D) the mediated by various coactivators and corepressors, and that imposition of a carbonyl ‘‘hinge’’ between the basic amine- the nature of these interactions may be dependent on the containing side chain and the olefin. In this paper we directly specific ligand that is bound to the receptor allows for the compare the in vitro and in vivo pharmacology of a series of possibility of ligand-based transcriptional control (5–8). In- compounds that separately address each of these structural deed, it has been hypothesized that a series of ligand- features. We demonstrate that individual elements of raloxifene’s dependent conformations exist and that each of these confor- molecular structure are responsible for its enhanced tissue selec- mations may influence a unique subset of estrogen-responsive tivity relative to tamoxifen; that changes in these structural genes (9, 10). A logical extension of this hypothesis is the elements affect the profile of biological activities that previously dependence of ER conformation on the structural features and have been described for raloxifene; and that one of these struc- tural elements causes raloxifene to assume a distinct molecular The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in This paper was submitted directly (Track II) to the Proceedings office. accordance with 18 U.S.C. §1734 solely to indicate this fact. Abbreviation: ER, estrogen receptor. © 1997 by The National Academy of Sciences 0027-8424y97y9414105-6$2.00y0 *To whom reprint requests should be addressed. e-mail: grese@ PNAS is available online at http:yywww.pnas.org. lilly.com. 14105 Downloaded by guest on September 28, 2021 14106 Pharmacology: Grese et al. Proc. Natl. Acad. Sci. USA 94 (1997) Table 2. Comparative effects on in vivo estrogen antagonism for various basic side chain modifications in the raloxifene nucleus In Vivo estrogen antagonism, maximal percent inhibition Compound R (Uterine wtybody wt) Tamoxifen 48* 1 91* 1g 81* FIG. 1. ER ligands tamoxifen and raloxifene. Differentiating struc- tural features are highlighted. 1h 3.8 conformation, which may, in turn, impact the conformation of the ER-raloxifene complex and in so doing be responsible for the unique tissue selectivity evidenced by this ER modulator. 1i 10 MATERIALS AND METHODS Chemistry. The compounds shown in Table 1 were prepared as previously described (23). Analogs bearing side-chain varia- tions, shown in Table 2, were prepared by Friedel–Crafts acyla- 1j 38* tion of 2-[4-methoxyphenyl]-6-methoxybenzothiophene with anisoyl chloride followed by selective O-demethylation and alky- lation of the resulting phenol with the appropriate electrophile 1k 36* under basic or Mitsunobu conditions (24, 25). Deprotection with y *Statistical significance relative to ethynyl estradiol-treated control ethanethiol aluminum chloride provided the target compounds. # Compound 2 (see Fig. 6) was prepared by a modification of the (P 0.05). method of Crenshaw involving the acid-mediated cyclization of 1 a compounds were fully characterized by H-NMR, mass spectra, an appropriately substituted -arylthiodeoxybenzoin (26). Com- andyor elemental analysis. Tamoxifen, 17a-ethynyl estradiol, and pound 3 (see Fig. 6) was prepared from a suitably protected 17b-estradiol were purchased from commercial sources. 11-thiacoumestrol by a method analogous to that described ER Binding. Affinity to the ER was determined in MCF-7 previously for coumestrol (27). Thus 3,9-dimethoxy-11- cell lysates by standard methods (29). Relative binding affin- thiacoumestan (28) was demethylated and converted to the b y ities were calculated as IC50 17 -estradiol IC50 compound. corresponding bis(tert-butyldimethylsilyl)ether. Low temperature MCF-7 Cell Proliferation. Effects on cellular proliferation reduction with diisobutylaluminum hydride followed by conden- were determined by standard methods (29) in MCF-7 breast sation of the resultant lactol with phenol provided the interme- adenocarcinoma cells. Cell cultures were treated in triplicate
Recommended publications
  • Pharmacology Risk Report
    Evidence Report: Risk of Therapeutic Failure Due to Ineffectiveness of Medication Virginia E. Wotring Ph. D. Universities Space Research Association, Houston, TX Human Research Program Human Health Countermeasures Element Approved for Public Release: August 02, 2011 National Aeronautics and Space Administration Lyndon B. Johnson Space Center Houston, Texas 2 TABLE OF CONTENTS I. PRD RISK TITLE: RISK OF THERAPEUTIC FAILURE DUE TO INEFFECTIVENESS OF MEDICATION ..................................................................... 6 II. EXECUTIVE SUMMARY .............................................................................................. 6 III. INTRODUCTION ............................................................................................................ 7 IV. PHARMACOK INETICS ............................................................................................... 11 A. Absorption ...................................................................................................................... 11 1. Evidence ................................................................................................................................ 16 2. Risk ........................................................................................................................................ 20 3. Gaps ....................................................................................................................................... 21 B. Distribution ....................................................................................................................
    [Show full text]
  • The In¯Uence of Medication on Erectile Function
    International Journal of Impotence Research (1997) 9, 17±26 ß 1997 Stockton Press All rights reserved 0955-9930/97 $12.00 The in¯uence of medication on erectile function W Meinhardt1, RF Kropman2, P Vermeij3, AAB Lycklama aÁ Nijeholt4 and J Zwartendijk4 1Department of Urology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; 2Department of Urology, Leyenburg Hospital, Leyweg 275, 2545 CH The Hague, The Netherlands; 3Pharmacy; and 4Department of Urology, Leiden University Hospital, P.O. Box 9600, 2300 RC Leiden, The Netherlands Keywords: impotence; side-effect; antipsychotic; antihypertensive; physiology; erectile function Introduction stopped their antihypertensive treatment over a ®ve year period, because of side-effects on sexual function.5 In the drug registration procedures sexual Several physiological mechanisms are involved in function is not a major issue. This means that erectile function. A negative in¯uence of prescrip- knowledge of the problem is mainly dependent on tion-drugs on these mechanisms will not always case reports and the lists from side effect registries.6±8 come to the attention of the clinician, whereas a Another way of looking at the problem is drug causing priapism will rarely escape the atten- combining available data on mechanisms of action tion. of drugs with the knowledge of the physiological When erectile function is in¯uenced in a negative mechanisms involved in erectile function. The way compensation may occur. For example, age- advantage of this approach is that remedies may related penile sensory disorders may be compen- evolve from it. sated for by extra stimulation.1 Diminished in¯ux of In this paper we will discuss the subject in the blood will lead to a slower onset of the erection, but following order: may be accepted.
    [Show full text]
  • MICHAEL J. WELCH, Ph.D. Personal Information
    CURRICULUM VITAE – MICHAEL J. WELCH, Ph.D. Personal Information: a. Sex: Male b. Birth date: 28 June 1939 c. Birthplace: Stoke-on-Trent, England Citizenship: USA__X__ Other____ Addresses and Telephone Numbers: Office: Division of Radiological Sciences Department of Radiology Washington University School of Medicine 510 South Kingshighway Blvd. Campus Box 8225 St. Louis, Missouri 63110 USA 314-362-8436 314-362-8399 fax Home: 312 N. Meramec #200 St. Louis, MO 63105 314-727-1550 Present Positions: Professor of Radiology Professor of Chemistry Professor of Developmental Biology Professor of Biomedical Engineering Washington University in St. Louis Education: Undergraduate: B.A. Degree in Natural Sciences – Cambridge University, England, 1961 Graduate: M.A. Degree in Natural Sciences – Cambridge University, England, 1964 Ph.D. Degree Chemistry – University of London, England, 1965 1 Academic Position/Employment: 9/62 - 8/65 Graduate Student Queen Mary College Department of Chemistry University of London London, England 9/65 - 9/67 Research Associate Brookhaven National Laboratory Upton, New York 9/67 - 7/70 Assistant Professor of Radiation Chemistry The Edward Mallinckrodt Institute of Radiology Washington University School of Medicine St. Louis, Missouri 9/69 - 1/71 Assistant Professor of Chemistry Department of Chemistry Washington University St. Louis, Missouri 7/70 - 7/74 Associate Professor of Radiation Chemistry The Edward Mallinckrodt Institute of Radiology Washington University School of Medicine St. Louis, Missouri 1/71 - 7/75 Associate Professor of Chemistry Department of Chemistry Washington University St. Louis, Missouri 7/75 - 7/78 Adjunct Professor Department of Chemistry Washington University St. Louis, Missouri 7/74 - 1991 Professor of Radiation Chemistry The Edward Mallinckrodt Institute of Radiology Washington University School of Medicine St.
    [Show full text]
  • Diverse Signaling Pathways Modulate Nuclear Receptor Recruitment of N-Cor and SMRT Complexes (Estrogen Receptor͞tamoxifen͞corepressor Complex)
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 2920–2925, March 1998 Biochemistry Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes (estrogen receptorytamoxifenycorepressor complex) ROBERT M. LAVINSKY*†,KRISTEN JEPSEN*†,THORSTEN HEINZEL*, JOSEPH TORCHIA*, TINA-MARIE MULLEN‡, RACHEL SCHIFF§,ALFONSO LEON DEL-RIO*, MERCEDES RICOTE¶,SALLY NGO¶,JOSLIN GEMSCH‡, SUSAN G. HILSENBECK§,C.KENT OSBORNE§,CHRISTOPHER K. GLASS¶,MICHAEL G. ROSENFELD*, \ AND DAVID W. ROSE‡ *Howard Hughes Medical Institute, ¶Cellular and Molecular Medicine, ‡Whittier Diabetes Program, and †UCSD Graduate Program in Biology, Department and School of Medicine, University of California at San Diego, La Jolla, CA 92093-0648; and §Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78284-7884 Contributed by Michael G. Rosenfeld, January 9, 1998 ABSTRACT Several lines of evidence indicate that the partial agonistic activity (31). Various agents that raise intra- nuclear receptor corepressor (N-CoR) complex imposes li- cellular cAMP levels or stimulate the rasyMAP kinase path- gand dependence on transcriptional activation by the retinoic way can similarly cause estrogen receptor (ER) activation in acid receptor and mediates the inhibitory effects of estrogen the presence of tamoxifen or the absence of any activating receptor antagonists, such as tamoxifen, suppressing a con- ligand (9, 32–35). In this manuscript we show that diverse stitutive N-terminal, Creb-binding proteinycoactivator com- molecular strategies regulate the association of N-CoR- or plex-dependent activation domain. Functional interactions SMRT-containing complexes with specific nuclear receptors, between specific receptors and N-CoR or SMRT corepressor including the nature of the ligand, the levels of available complexes are regulated, positively or negatively, by diverse N-CoRySMRT, and the action of diverse protein kinase- signal transduction pathways.
    [Show full text]
  • A Unique Estrogen Receptor-Regulated Gene That Is Activated by Antiestrogens (Electrophile Response Element͞tamoxifen͞antioxidant͞breast Cancer)
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 2581–2586, March 1997 Medical Sciences The quinone reductase gene: A unique estrogen receptor-regulated gene that is activated by antiestrogens (electrophile response elementytamoxifenyantioxidantybreast cancer) MONICA M. MONTANO* AND BENITA S. KATZENELLENBOGEN*†‡ *Departments of Molecular and Integrative Physiology and †Cell and Structural Biology, University of Illinois and College of Medicine, Urbana, IL 61801-3704 Communicated by Jack Gorski, University of Wisconsin, Madison, WI, December 30, 1996 (received for review October 4, 1996) ABSTRACT Antiestrogens are thought to exert most of 10 and 11). These widely distributed enzymes detoxify elec- their beneficial effects in breast cancer by antagonizing the trophiles, thereby protecting cells against the toxic and neo- actions of estrogen. We report here that antiestrogens also plastic effects of carcinogens. stimulate the expression of quinone reductase (QR) [NAD- Using the technique of RNA differential display (12), we (P)H:quinone oxidoreductase, EC 1.6.99.2], which may pro- have identified in this report QR mRNA as a species that is vide protective effects against the toxicity and mutagenicity expressed at much higher levels in an MCF-7 breast cancer cell caused by quinones. QR is up-regulated by low concentrations subline that has been grown long term in the presence of the of antiestrogens (trans-hydroxytamoxifen, tamoxifen, and antiestrogen trans-hydroxytamoxifen (TOT) (13). We there- ICI182,780) in estrogen receptor (ER)-containing breast can- fore undertook the examination of its regulation by antiestro- cer cells, and this increase is suppressed by estrogen via an gens as a possible basis for the proposed antioxidant action of ER-dependent mechanism.
    [Show full text]
  • STEROID RECEPTORS in HEALTH and DISEASE SERONO SYMPOSIA, USA Series Editor: James Posillico
    STEROID RECEPTORS IN HEALTH AND DISEASE SERONO SYMPOSIA, USA Series Editor: James Posillico ACROMEGALY: A Century of Scientific and Clinical Progress Edited by Richard J. Robbins and Shlomo Melmed BASIC AND CLINICAL ASPECTS OF GROWTH HORMONE Edited by Barry B. Bercu THE PRIMATE OVARY Edited by Richard L. Stouffer SOMATOSTATIN: Basic and Clinical Status Edited by Seymour Reichlin STEROID RECEPTORS IN HEALTH AND DISEASE Edited by Virinder K. Moudgil A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further infor­ mation please contact the publisher. STEROID RECEPTORS IN HEALTH AND DISEASE Edited by Virinder K. Moudgil Oakland University Rochester, Michigan PLENUM PRESS • NEW YORK AND LONDON library of Congress Cataloging in Publication Data Meadow Brook Conference on Steroid Receptors in Health and Disease (tst(tst:: t987 : Rochester, Mich .) Ste roid receptors in health and disease / edited by Virinder K. Moudgil. p. cm . "Proc" Proceedingseedings of the Meadow Brook Conference on Steroid Receptors in Health and Disease, spon­ sored by Serono Symposia. USA and Oakland University. held September 20-23, 19871987.. in Rochester. Michigan ··-T.p. verso. Includes bibliographies and indexes. IS8N 978-1-4684-5543-4 IS8N 978-1-4684-5541-0 (eBook) 00110.1007/978-1-4684-5541-0 I . Steroid hormones-Receptors-Congresses. 1. Moudgil, V.V. K.K. (Virinder K.), 1945- . 11. Sereno Symposia, USA. III.Ill. Oakland Universityly. IV. Title. [oNlM[oNlM:: tt. Receptors , Sleroid-congresses. W3 ME3781st 1987s / WK 150 M482 1987sJ1987sj oP571.7.M42 1987 512 '.
    [Show full text]
  • Workshop 1.4 Nature of the Ligand-Binding Pocket
    Pure Appl. Chem., Vol. 75, Nos. 11–12, pp. 2397–2403, 2003. © 2003 IUPAC Workshop 1.4 Nature of the ligand-binding pocket of estrogen receptor a and b: The search for subtype- selective ligands and implications for the prediction of estrogenic activity* John A. Katzenellenbogen‡, Rajeev Muthyala, and Benita S. Katzenellenbogen Departments of Chemistry, Molecular and Integrative Physiology, University of Illinois, Urbana, 61801 IL, USA Abstract: The ligand-binding pockets of estrogen receptor alpha and beta (ERα and ERβ) ap- pear to have subpockets of different size and flexibility. To find ligands that will discriminate between the two ER subtypes on the basis of affinity or efficacy, we have prepared com- pounds of varying size, shape, and structure. We have evaluated the binding affinity of these compounds and their potency and efficacy as transcriptional activators through ERα and ERβ. In this manner, we have identified a number of ligands that show pronounced ER sub- type selectivity. These studies also highlight the eclectic structure–activity relationships of estrogens and the challenges inherent in developing computational methods for the predic- tion of estrogenic activity. INTRODUCTION The actions of estrogens are mediated by the estrogen receptor (ER), an intracellular protein that func- tions as a ligand-regulated transcription factor [1]. There are two subtypes of the estrogen receptor, ER α and ERβ; these subtypes have different tissue distributions and are thought to regulate different estro- gen responses [2]. Therefore, ligands that are selective in activating or inhibiting these two subtypes could have a desirable pattern of pharmacological activity that might be useful in regulating fertility, in treating menopausal symptoms, and in preventing and treating breast cancer [1].
    [Show full text]
  • Deciphering Molecular Mechanisms of Adverse Reactions of Drugs
    UNIVERSITY OF CALIFORNIA, SAN DIEGO Deciphering Molecular Mechanisms of Adverse Reactions of Drugs A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioinformatics and Systems Biology by Yu-Chen Chen Committee in charge: Professor Ruben Abagyan, Chair Professor Grace M. Kuo, Co-Chair Professor Nuno F. Bandeira Professor Sanjoy Dasgupta Professor Lucila Ohno-Machado 2014 Copyright Yu-Chen Chen, 2014 All rights reserved. Signature Page The Dissertation of Yu-Chen Chen is approved, and it is acceptable in quality and form for publication on microfilm and electronically: _____________________________________________________________________ _____________________________________________________________________ _____________________________________________________________________ _____________________________________________________________________ Co-Chair _____________________________________________________________________ Chair University of California, San Diego 2014 iii TABLE OF CONTENTS Table of Contents Signature Page ............................................................................................................... iii Table of Contents .......................................................................................................... iv List of Figures ................................................................................................................ ix List of Tables ...............................................................................................................
    [Show full text]
  • Therapeutic Implications and Challenges Towards Drug Discovery. J Nanotechnol Nanomaterials
    https://www.scientificarchives.com/journal/journal-of-nanotechnology-and-nanomaterials Journal of Nanotechnology and Nanomaterials Short Communication CO-Releasing Materials: Therapeutic Implications and Challenges towards Drug Discovery Muhammad Faizan1, Niaz Muhammad2* 1Key Laboratory of Applied Surface and Colloid Chemistry MOE, School of Chemistry and Chemical Engineering, Shaanxi Nor- mal University, Xi’an 710062, China 2Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi’an 710062, China *Correspondence should be addressed to Niaz Muhammad; [email protected] Received date: August 05, 2019, Accepted date: September 16, 2019 Copyright: © 2020 Faizan M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Keywords: CO administration; CO-releasing materials; been raised significantly beyond the therapeutic level CO-releasing molecules; Therapeutic agent; Organometallic because CO gas has great affinity with hemoglobin to complexes; Synovial joints form the carboxy hemoglobin (COHb). The percentage of COHb above 10% (therapeutic level) contains the CO: Carbon Monoxide; HO: Heme Abbreviations: oxygen movement along blood circulation [7]. This issue Oxygenase; COHb: Carboxy Hemoglobin; CORMats: CO- has been addressed properly through indirect inhalation. Releasing Materials; CORMs: CO-Releasing Molecules Indirect inhalation strategy has been further divided into Introduction two categories i.e. CO-releasing molecules (CORMs) and CO-releasing materials (CORMats) [8]. Since last century, carbon monoxide (CO) generally regarded as “silent killer” and life-threatening for living CORMs are organometallic carbonyl complexes organisms because of its colourless, odourless and good for solubility and shown good compatibility with poisonous nature [1].
    [Show full text]
  • Recent Emergence of Rhenium(I) Tricarbonyl Complexes As Photosensitisers for Cancer Therapy
    molecules Review Recent Emergence of Rhenium(I) Tricarbonyl Complexes as Photosensitisers for Cancer Therapy Hui Shan Liew 1, Chun-Wai Mai 2,3 , Mohd Zulkefeli 3, Thiagarajan Madheswaran 3, Lik Voon Kiew 4, Nicolas Delsuc 5 and May Lee Low 3,* 1 School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; [email protected] 2 Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; [email protected] 3 School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; [email protected] (M.Z.); [email protected] (T.M.) 4 Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; [email protected] 5 Laboratoire des Biomolécules, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, 75005 Paris, France; [email protected] * Correspondence: [email protected]; Tel.: +60-3-27317694 Academic Editor: Kogularamanan Suntharalingam Received: 8 July 2020; Accepted: 23 July 2020; Published: 12 September 2020 Abstract: Photodynamic therapy (PDT) is emerging as a significant complementary or alternative approach for cancer treatment. PDT drugs act as photosensitisers, which upon using appropriate wavelength light and in the presence of molecular oxygen, can lead to cell death. Herein, we reviewed the general characteristics of the different generation of photosensitisers. We also outlined the emergence of rhenium (Re) and more specifically, Re(I) tricarbonyl complexes as a new generation of metal-based photosensitisers for photodynamic therapy that are of great interest in multidisciplinary research. The photophysical properties and structures of Re(I) complexes discussed in this review are summarised to determine basic features and similarities among the structures that are important for their phototoxic activity and future investigations.
    [Show full text]
  • Molecular and Preclinical Pharmacology of Nonsteroidal Androgen Receptor Ligands
    Molecular and Preclinical Pharmacology of Nonsteroidal Androgen Receptor Ligands Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Amanda Jones, M.S. Graduate Program in Pharmacy The Ohio State University 2010 Dissertation Committee: James T. Dalton, Advisor Thomas D. Schmittgen William L. Hayton Robert W. Brueggemeier Copyright by Amanda Jones 2010 Abstract The androgen receptor (AR) is critical for the growth and development of secondary sexual organs, muscle, bone and other tissues, making it an excellent therapeutic target. Ubiquitous expression of AR impedes the ability of endogenous steroids to function tissue selectively. In addition to the lack of tissue selectivity, clinical use of testosterone is limited due to poor bioavailability and pharmacokinetic problems. Our lab, in the last decade, discovered and developed tissue selective AR modulators (SARMs) that spare androgenic effects in secondary sexual organs, but demonstrate potential to treat muscle wasting diseases. This work reveals the discovery of next generation SARMs to treat prostate cancer and mechanistically characterize a prospective SARM in muscle and central nervous system (CNS). Prostate cancer relies on the AR for its growth, making it the primary therapeutic target in this disease. However, prolonged inhibition, with commercially available AR antagonists, leads to the development of mutations in its ligand binding domain resulting in resistance. Utilizing the crystal structure of AR-wild-type and AR-W741L mutant, we synthesized a series of AR pan- antagonists (that inhibit both wild-type and mutant ARs). Structure activity relationship studies indicate that sulfonyl and amine linkages of the aryl propionamide pharmacophore are important for the antagonist activity.
    [Show full text]
  • Tissue Selectivity in Multiple Endocrine Neoplasia Type 1-Associated Tumorigenesis Ana Gracanin,1 Koen M
    Published OnlineFirst August 4, 2009; DOI: 10.1158/0008-5472.CAN-09-0678 Review Tissue Selectivity in Multiple Endocrine Neoplasia Type 1-Associated Tumorigenesis Ana Gracanin,1 Koen M. A. Dreijerink,2,3 Rob B. van der Luijt,4 Cornelis J. M. Lips,3 and Jo W. M. Ho¨ppener5,6 1Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University; Departments of 2Physiological Chemistry, 3Internal Medicine and Endocrinology, 4Medical Genetics, and 5Metabolic and Endocrine Diseases, University Medical Center Utrecht; and 6Netherlands Metabolomics Center, Utrecht, The Netherlands Abstract menin, has functions in DNA stability and gene regulation and The phenotype of the multiple endocrine neoplasia type 1 can function as a tumor suppressor (4). However, the ubiquitous (MEN1) syndrome cannot be explained solely by the expres- nature of menin expression fails to explain the predominant sion pattern of the predisposing gene MEN1 and its encoded endocrine phenotype of MEN1 and its variable clinical manifes- protein, menin. This reviewaddresses putative factors tation. The diversity of organs and/or tissues affected in MEN1 determining MEN1-associated tissue-selective tumorigenesis. might suggest a very early defect during embryonal develop- Menin’s interaction with mixed-lineage leukemia protein- ment. In agreement with this notion, menin-deficient mouse containing histone methyl transferase (MLL-HMT) complex embryos develop abnormalities in multiple endocrine and mediates tissue-selective tumor-suppressing and
    [Show full text]