David T. Mao

University Center Rochester, Rochester, Minnesota, United States

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Publications (5)24.34 Total impact

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    ABSTRACT: Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193) is a C-glycosyl thiazole nucleoside with antitumor activity. Crystal structures of tiazofurin and its alpha,2'-deoxy and xylo analogues all show close contacts between the thiazole sulfur (S) and the furanose ring oxygen (O1'). These contacts have been interpreted in terms of an attractive intramolecular S-O interaction in the thiazole nucleosides. Ara-tiazofurin (2-beta-D-arabinofuranosylthiazole-4-carboxamide, ara-T) is the inactive arabinose analogue of tiazofurin. The crystal structure of ara-T is reported. This structure provides evidence for an attractive S-O interaction not seen in the other thiazole nucleosides. The conformation about the C-glycosyl bond in ara-T is such that close contacts are formed between the thiazole sulfur and both O1' and the 2'-hydroxyl oxygen O2'. This conformation is interpreted in terms of an additional attractive interaction between S and O2'. This interpretation is supported by comparison of the conformation of ara-T with those of other ara-nucleosides. These findings provide further evidence for an attractive S-O interaction in the thiazole nucleosides. Ara-T also demonstrates a second conformational feature found in these compounds: the carboxamide nitrogen remains cis to the thiazole nitrogen. Implications of these potentially constrained conformational features are discussed in terms of the mechanism of activity of tiazofurin.
    No preview · Article · Jun 1988 · Journal of Medicinal Chemistry
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    ABSTRACT: One of the problems encountered in the use of tetrahydrouridine (THU, 2) and saturated 2-oxo-1,3-diazepine nucleosides as orally administered cytidine deaminase (CDA) inhibitors is their acid instability. Under acid conditions these compounds are rapidly converted into inactive ribopyranoside forms. A solution this problem was sought by functionalizing the acid-stable but less potent CDA inhibitor 1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (1) with the hope of increasing its potency to the level achieved with THU. The selection of the hydroxymethyl substituent at C-4, which led to the synthesis of 4-(hydroxymethyl)-1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (10), 3,4-dihydro-4-(hydroxymethyl)-1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (7), and 3,4,5,6-tetrahydro-4-(dihydroxymethyl)-1-beta-D-ribofuranosyl-2(1H)-p yrimidinone (28) was based on the transition-state (TS) concept. The key intermediate precursor, 4-[(benzoyloxy)methyl]-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-2(H) -pyrimidinone (24), was obtained via the classical Hilbert-Johnson reaction between 2-methoxy-4-[(benzoyloxy)methyl]pyrimidine (20) and 2,3,5-tri-O-benzoyl-1-D-ribofuranosyl bromide (21). Deprotection of 24 afforded compound 10, while its sodium borohydride reduction products afforded compounds 7 and 28 after removal of the blocking groups. Syntheses of 3,4-dihydro-1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (9) and 3,6-dihydro-1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (8), which lack the hydroxymethyl substituent, was accomplished in a similar fashion. The new compounds bearing the hydroxymethyl substituent were more acid stable than THU, and their CDA inhibitory potency, expressed in terms of Ki values, spanned from 10(-4) to 10(-7) M in a manner consistent with the TS theory. Compound 7, in particular, was superior to its parent 1 and equipotent to THU (Ki = 4 X 10(-7) M) when examined against mouse kidney CDA. The superior acid stability of this compound coupled to its potent inhibitory properties against CDA should provide a means of testing oral combinations of rapidly deaminated drugs, viz. ara-C, without the complications associated with the acid instability of THU.
    No preview · Article · Sep 1986 · Journal of Medicinal Chemistry
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    ABSTRACT: Tiazofurin (TR), a new antitumor agent, enters human erythrocytes by utilizing their facilitated nucleoside transport system. TR competes with endogenous nucleosides for this transport mechanism, thereby reducing nucleoside uptake into the cells. Pre-incubation of erythrocytes for 10 min at 22 degrees C with 100 microM and 500 microM TR reduced the transport of 14C-uridine into the cells by 27% and 74%, respectively. Simultaneous exposure of cells to TR and [14C]uridine did not alter the inhibitory effect of TR. Furthermore, the transport inhibitory effect of TR was lost when cells were washed twice with Hanks basal salt solution following a 10-min pre-incubation with TR. The Km and Vmax (+/- S.E.) for radiolabeled TR transport into erythrocytes are 170 +/- 26 microM and 55 +/- 13 nmol/h per 10(6) cells, respectively, which is similar to the kinetic constants measured for uridine transport into erythrocytes (Km = 168 +/- 37 microM and Vmax = 61 +/- 16 nmol/h per 10(6) cells). The Ki (+/- S.E.) of TR for uridine transport is 178 +/- 11 microM and for thymidine transport is 102 +/- 59 microM. Three analogues of TR (its selenium isostere (SR), and Ara (Ara-TR) and Xylo (Xylo-TR) derivatives) were compared with TR for their ability to compete with and inhibit uridine transport, as these analogues were not available in a radiolabeled form for direct measurement of their transport into the cell. SR had similar kinetic characteristics of inhibition of uridine transport to TR (Ki = 145 +/- 15 microM) but Ara-TR had a Ki = 1.04 +/- 0.13 mM while Xylo-TR inhibited uridine transport with a Ki = 1.57 +/- 0.67 mM. Thus, TR is transported into erythrocytes with the same velocity and affinity for the carrier as uridine and competitively inhibits nucleoside transport into the cell. Of 3 other C-nucleoside derivatives examined, SR is of similar potency to TR but Ara-TR and Xylo-TR are much less effective at competing with uridine for the nucleoside transporter.
    Full-text · Article · Sep 1985 · Cancer Letters
  • David T. Mao · Victor E. Marquez
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    ABSTRACT: The syntheses of the heretofore unknown 2-β-D-ara and 2-β-D-xylofuranosyl isomers of the antitumor agent tiazofurin have been accomplished. In both cases the stereospecific inversion of the required 2′ or 3′-hydroxyl group in the protected parent compound afforded the desired products.
    No preview · Article · Dec 1984 · Tetrahedron Letters
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    David T. Mao · John S. Driscoll · Victor E. Marquez
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    ABSTRACT: The ribo- and arabinofuranosyl nucleosides of antitumor active 2- and 4-pyridones 1a and 2a were prepared by direct condensation of the silylated bases with either 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (4a) or 2,3,5-tri-O-benzyl-1-p-nitrobenzoyl-D-arabinofuranose (7) in the presence of trimethylsilyl triflate (Me3SiOTf). In the case of the arabinofuranosyl nucleosides, separation of the alpha and beta anomers was accomplished at the stage of O-benzyl-protected compounds (8b + 9b, and 10b + 11b) after chemical functionalization of the 3-hydroxy group of the pyridone aglycons with acetyl and benzyl groups, respectively. Deblocking of the protected ribo- and arabinofuranosyl nucleosides was performed by the standard methods. In vitro activity against P-388 cells in culture indicated that the 4-pyridone riboside 6d was the most active member of the series with a twofold lower ID50 than the parent pyridone 2a. However, this and all the other compounds tested in this series showed no activity against the in vivo model system of murine P-388 leukemia at doses ranging from 25 to 400 mg/kg qd 1-5.
    Preview · Article · Mar 1984 · Journal of Medicinal Chemistry

Publication Stats

151 Citations
24.34 Total Impact Points

Institutions

  • 1988
    • University Center Rochester
      • Department of Biophysics
      Rochester, Minnesota, United States
  • 1984-1985
    • National Institutes of Health
      • • Program of Developmental Therapeutics
      • • Chemical Biology Laboratory
      Maryland, United States