title: Pure enantiomers of benzoylamino-tranylcypromine: LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts.
abstract: The pure enantiomers of the N-(2-, 3-, and 4-(2-aminocyclopropyl)phenyl)benzamides hydrochlorides 11a-j were prepared and tested against LSD1 and MAO enzymes. The evaluation of the regioisomers 11a-j highlighted a net increase of the anti-LSD1 potency by shifting the benzamide moiety from ortho to meta and mainly to para position of tranylcypromine phenyl ring, independently from their trans or cis stereochemistry. In particular, the para-substituted 11a,b (trans) and 11g,h (cis) compounds displayed LSD1 and MAO-A inhibition at low nanomolar levels, while were less potent against MAO-B. The meta analogs 11c,d (trans) and 11i,j (cis) were in general less potent, but more efficient against MAO-A than against LSD1. In cellular assays, all the para and meta enantiomers were able to inhibit LSD1 by inducing Gfi-1b and ITGAM gene expression, with 11b,c and 11g-i giving the highest effects. Moreover, 11b and 11g,h strongly inhibited the clonogenic potential of murine promyelocytic blasts.
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Rodriguez
authors.affiliation: Genextra Group, DAC s.r.l. Via Adamello 16, 20139 Milano, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.affiliation: Dipartimento di Oncologia Sperimentale, IEO - European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vianello
authors.affiliation: Italian National Institute of Health, Department of Therapeutic Research and Medicines Evaluation, Via Regina Elena 299, 00161 Roma, Italy.
authors.forename: Bruna
authors.initials: B
authors.lastname: Saponara
authors.affiliation: Italian National Institute of Health, Department of Therapeutic Research and Medicines Evaluation, Via Regina Elena 299, 00161 Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciossani
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Labella
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Biagina
authors.initials: B
authors.lastname: Marrocco
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Monaldi
authors.affiliation: Department of Sense Organs, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ruoppolo
authors.affiliation: Centre of Theoretical and Computational Chemistry (CTCC), Department of Chemistry, P.O. Box 1033, Blindern, N-0315 Oslo, Norway.
authors.forename: Mats
authors.initials: M
authors.lastname: Tilset
authors.affiliation: Dipartimento di Oncologia Sperimentale, IEO - European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy.
authors.forename: Oronza A
authors.initials: OA
authors.lastname: Botrugno
authors.affiliation: Dipartimento di Oncologia Sperimentale, IEO - European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dessanti
authors.affiliation: Dipartimento di Oncologia Sperimentale, IEO - European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy; Department of Biosciences, University of Milan, 20100 Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.affiliation: Dipartimento di Oncologia Sperimentale, IEO - European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy; Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy. Electronic address: antonello.mai@uniroma1.it.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine; D056466:Histone Demethylases; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human; C495195:KDM1A protein, human
keywords: Epigenetics; Leukemia; Lysine-specific demethylase 1; Stereoisomers; Tranylcypromine