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Analogues of Azepinomycin: Inhibitors ofGuanaseAnila Bhan a & Ramachandra S. Hosmane aa Laboratory for Drug Design and Synthesis Department of Chemistry,Biochemistry University of Maryland Baltimore County, Baltimore,Maryland, 21228Published online: 16 Feb 2007.

To cite this article: Anila Bhan & Ramachandra S. Hosmane (1995): Analogues of Azepinomycin:Inhibitors of Guanase, Nucleosides and Nucleotides, 14:3-5, 455-458

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NUCLEOSIDES & NUCLEOTIDES, 14(3-5), 455-458 (1995)

ANALOGUES OF AZEPINOMYCIN INHIBITORS OF GUANASE

Anila Bhan and Ramachandra S. Hoemane* Laboratory for Drug Design and Synthesis

Department of Chemistry and Biochemistry University of Maryland Baltimore County, Baltimore, Maryland 2 1228

ABSTRACT

Synthesis and guanase inhibitory activity of two novel 5:7-@ed heterocyles, 15 and 16, containing the imidazo[4,5-elll ,Ildiazepine ring system, have been reported.

INTRODUCTION

Guanase catalyzes the hydrolysis of guanine to xanthine (Scheme I) via the

putative sequence of intermediates, collectively depicted as 1.' Azepinomycin (2) is a

a b c

1 0 0 0

H H H H 2 3 4

SCHEME I

455

Copyright 0 1995 by Marcel Dekker, Inc.

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456 BHAN AND HOSMANE

naturally occurring antitumor antibiotic, and is considered to be the transition state analogue inhibitor of this enzyme.2 However, an examination of 1 reveals that both la and lc contain a quaternary carbon at the 2-position, the site of hydrolysis, with geminal thio/amlno or thiolhydroxy functionalities. Therefore, a more appropriate inhibitor to mimic the transition state of the deaminase reaction might be a compound such as 3 or 4 having a quaternary carbon attached to two substituents a t the 6- position of the imidazo[4.5-el[ 1,4ldiazepine ring, as contrasted with azepinomycin that lacks such a quaternary carbon. We report here the synthesis and biochemical screening of two compounds, 15 and 16, which incorporate this important structural characteristic of 3 and 4 that is missing in azepinomycin.

A retrosynthetic analysis of 3 and 4 called for a synthon such as 6 and 6 which contain a unique diamino- or alkoqaminomalonate side chain, and for which there is little literature precedent. A logicql precursor to both 6 and 6 is the aminomalonate derivative 7.3 Oxidation of 7 to produce the iminomalonate intermediate 8, followed by conjugate addition by an amine or alkoxy nucleophfle would yield the desired diamino- and alkoxyaminomalonate synthons 6 and 6, respectively. Indeed, bromination of 7 in the presence of sodium hydride, followcd by quenching with benzylamine or methanol, afforded the desired 9 (mp 100- 101 "C), (10; mp 126- 127 "C), respectively (Scheme XI). Reduction of 9 and 10 with Pd-C/H, provided the respective 11 (mp 121-123 "C) and 12 (mp 162-163 "C). Treatment of 11 and 12 with sodium methoxide in refluxing methanol resulted in ring-closure with concomitant exchange of the ester ethodde group

U2N ' - I R"

5 6

ROH L 6 7 L 8 1

R = Et, R" = CH2Ph

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AZEPINOMYCIN ANALOGUES 457

CyPh

10

80% Pd-C (10%) / H2 1 MeOH

0 OZN I PhCH:

8

12

1) NaOMe I MeOH 2) Pd(Ow2 / CH3C02H

0

9

Pd-C (10%) I Hp 79% MeOH 1

2) Pd(0h)p / CH3CO2H 1) NaOMe/ MeOH

13, R = CH2Ph 15, R = H

14, R = CH2P h 16, R = H

SCHEME I1

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458 BHAN AND HOSMANE

with a methoxide to produce 13 and 14, respectively. Debenzylation of 13 and 14 with Pd(OH),/H, in acetic acid provided 16 (mp: sinters at 196 "C and 203 "C (d)) and 16 (mp >280 "C). The structures of both 15 and 10 were confirmed by single-crystal X-ray diffraction ana ly~is .~

Fhally, both 16 and 10 were screened In uttro against rabbit liver guanase in a Tris buffer (pH 7.6) at 2 1 "C, by spectrophotometrically monitoring the rate of hydrolysis of the substrate guanine at 248 nm. Both were found to be inhibitors of this enzyme with €$'s = 1.9 x M, respectively.

In view of the recent detection of abnormally high levels of guanase activity in

patients with liver diseases596 and those with multiple sc le r~s is ,~ the search for a suitable guanase inhibitor may be timely for exploration of the biochemical mechanism(s) of these disorders.

M and 5.4 x

ACKNOWLEDGMENTS

This research was supported by grants from the National Institutes of Health (#CA 36 154 and #GM 49249), and the Maryland IndustrialPartnershipProgram (#910).

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Nishimura. S.; Okada. N.: Tatsuta. K. J. Antiblot. 1987. 40. 146 1. (c) Fujii. T.: Saito, T.; Fufisawa, T. Heterocycles 1988. 27. 1163.

Bhan. A.: Hosmane. R. S. J. Heterocycl. Chem. 1993, 30, 1453.

The X-ray diffraction analyses of compounds 16 and 10 were performed at the Department of Chemistry. Southern Methodist University, Dallas. Texas by Dr. Hongming Zhang. and his assistance in this regard is gratefully acknowledged. (a) Nishikawa. Y.; Fukumoto, K.; Watanabe. F.; Yoshihara. H. Jpn. J. Clfn. Pathol. (RLmho Byorfl 1989, 37. 1392. (b) Shiota. G.; Fukuda, J.; Ito. T.; Tsukizawa, M.; Sato. M. Jpn. J.

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Gary. G.S.; Yasmlneh, W.G.; Snover. D.C.; Vine, W. Transplant Proc. 1989. 21, 23 15.

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