Studies on the synthesis and biological evaluation of certain pyrrolo[2,3-d] pyrimidine nucleosides and their methylated analogs which are structurally related to the naturally occurring nucleoside Q, nucleoside Q*, and methylated guanosines.

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Title Studies on the synthesis and biological evaluation of certain pyrrolo[2,3-d] pyrimidine nucleosides and their methylated analogs which are structurally related to the naturally occurring nucleoside Q, nucleoside Q*, and methylated guanosines.
Publication Type dissertation
School or College College of Pharmacy
Department Medicinal Chemistry
Author Cheng, Chin Shu.
Contributor Wotring, Linda L.
Date 1981-06
Description The synthesis of 7-cyano-7-deazguanosine (preQ(,0), 6) has been accomplished in our laboratory via a multi-step synthesis from the nucleoside antibiotic toyocamycin (1). This nucleoside has been subsequently established as a precursor of the naturally occurring nucleosides Q (8) and Q* (9). This finding prompted us to prepare several other preQ(,0) analogs. 7-Cyano-N('2),N('2)-dimethyl-7-deazaguanosine (150) was prepared by the treatment of 2-chloro-5-cyano-7-(2,3,5-tri-O-acetyl-(beta)-D-ribofuranosyl)pyrrolo{2,3,-d}pyrimidin-4-one (149) with ethanolic dimethylamine. The corresponding N('2)-methylguanosine analog 154 was not obtained either by the direct amination or several other alternative approaches. 7-Aminomethyl-7-deazaguanosine (preQ(,1), 7) has been isolated, characterized, and also established as being one of the precursors in the biosynthesis of the naturally occurring nucleosides Q (8) and Q* (9). This prompted us to prepare some closely related preQ(,1) analogs. Hence, 7-aminomethyl-7-deazaguanosine (7) was prepared by a catalytic hydrogenation of the corresponding 7-cyano-7-deazaguanosine derivative 6. The nucleoside preQ(,0) (6) and other closely related 7-cyano-7-deazaguanosine analogs were chemically converted to nucleosides with a carboxamido function at the 7-position. The significance of the proton residing on N-1 and the C-2 amino group of the 7-deazaguanosine derivatives in regards to antileukemic activity could be assessed by blocking the position(s) with methyl group(s). In addition, these derivatives can also be viewed as analogs of a specific class of naturally occurring, modified nucleosides, i.e., 1-methylguanosine (m('1)G) and N('2)-methylated guanosines (m('2)G, m(,2)('2)G). In an effort to expand the knowledge in this area of study, a series of N-1 and/or C-2 amino methylated quanosine derivatives, 7-cyano-7-deazaguanosine, 7-aminomethyl-7-deazaguanosine, and 7-carboxamido-7-deazaguanosine, were prepared by amination of 2-chloro-5-cyano-3-methyl-7-(2,3,5-tri-O-acetyl-(beta)-D-ribofuranosyl)pyrrolo-{2,3-d}pyrimidin-4-one (160). The transformation of cyano group to aminomethyl and carboxamido function by catalytic hydrogenation and with basic hydrogen peroxide, respectively, was also accomplished. The results from the in vitro cytotoxicity testing against leukemia L1210 cell line indicated that the proton residing on N-1 of 7-deazaguanosine analogs is necessary for intrinsic cytotoxicity in this series of compounds. Methylation at an amino group (position-2) decreases the cytotoxicity. The effect of different substituents at purine position-7 of 7-deazaguanosine derivatives was also observed, in general, in the following trend: cyano (TURNEQ) carboxamido >> aminomethyl.
Type Text
Publisher University of Utah
Subject RNA; Cytotoxicity
Subject MESH Guanosine; Nucleosides
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Studies on the synthesis and biological evaluation of certain pyrrolo[2,3-d] pyrimidine nucleosides and their methylated analogs which are structurally related to the naturally occurring nucleoside Q, nucleoside Q*, and methylated guanosines." Spencer S. Eccles Health Sciences Library. Print version of "Studies on the synthesis and biological evaluation of certain pyrrolo[2,3-d] pyrimidine nucleosides and their methylated analogs which are structurally related to the naturally occurring nucleoside Q, nucleoside Q*, and methylated guanosines." available at J. Willard Marriott Library Special Collection. QP 6.5 1981 C47.
Rights Management © Chin Shu Cheng.
Format application/pdf
Format Medium application/pdf
Identifier us-etd2,173
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship Department of Medicinal Chemistry, College of Pharmacy, University of Michigan.
ARK ark:/87278/s6c259vf
Setname ir_etd
ID 192113
Reference URL https://collections.lib.utah.edu/ark:/87278/s6c259vf
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