title: Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides.
abstract: Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.
authors.affiliation: Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, NY 10031, USA. ssakilam@ccny.cuny.edu.
authors.forename: Sakilam
authors.initials: S
authors.lastname: Satishkumar
authors.affiliation: Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, NY 10031, USA. vkumar@ccny.cuny.edu.
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Vuram
authors.affiliation: Discovery and Analytical Services, GVK Biosciences Pvt. Ltd., 28A IDA Nacharam, Hyderabad 500076, India. siva.relangi@gvkbio.com.
authors.forename: Siva Subrahmanyam
authors.initials: SS
authors.lastname: Relangi
authors.affiliation: Discovery and Analytical Services, GVK Biosciences Pvt. Ltd., 28A IDA Nacharam, Hyderabad 500076, India. venkateshwarlu.gurram@gvkbio.com.
authors.forename: Venkateshwarlu
authors.initials: V
authors.lastname: Gurram
authors.affiliation: Clinical Immunotherapy Section, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. hong.zhou@nih.gov.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Clinical Immunotherapy Section, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. kreitmar@mail.nih.gov.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kreitman
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe-School of Medicine, P. O. Box 60327, Bayamón, PR 00960, USA. mmmtz92@gmail.com.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Martínez Montemayor
authors.affiliation: Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, NY 10031, USA. lyang@sci.ccny.cuny.edu.
authors.forename: Lijia
authors.initials: L
authors.lastname: Yang
authors.affiliation: Discovery and Analytical Services, GVK Biosciences Pvt. Ltd., 28A IDA Nacharam, Hyderabad 500076, India. muralidharan.k@gvkbio.com.
authors.forename: Muralidharan
authors.initials: M
authors.lastname: Kaliyaperumal
authors.affiliation: Discovery and Analytical Services, GVK Biosciences Pvt. Ltd., 28A IDA Nacharam, Hyderabad 500076, India. somesh.sharma@gvkbio.com.
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Discovery and Analytical Services, GVK Biosciences Pvt. Ltd., 28A IDA Nacharam, Hyderabad 500076, India. narender.pottabathini@gvkbio.com.
authors.forename: Narender
authors.initials: N
authors.lastname: Pottabathini
authors.affiliation: Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, NY 10031, USA. mlakshman@ccny.cuny.edu.
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Lakshman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D017338:Cladribine / Q000138:chemical synthesis* / Q000494:pharmacology; D006151:Guanosine / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007943:Leukemia, Hairy Cell / Q000473:pathology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000473:pathology; D009943:Organophosphorus Compounds / Q000737:chemistry; D061251:Primary Cell Culture; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D006151:Guanosine; D017338:Cladribine; C031032:benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
keywords: (benzotriazol-1yl-oxy)-tris(dimethylamino)phosphonium hexafluorophosphate; BOP; benzotriazole; cladribine; guanosine; nucleoside