Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines

Joel A. Yalowitz, Krzysztof Pankiewicz, Steven E. Patterson, Hiremagalur N. Jayaram

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Mycophenolic acid (MPA) is a fungally-derived inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH). MPA binds IMPDH at the nicotinamide sub-site of the NAD cofactor binding domain leaving the adenosine sub-site empty. In order to improve the binding affinity we synthesized MPA analogs by linking adenosine 5′-methylenebis(phosphonate) with mycophenolic alcohols containing 2-, 4-, and 6-carbon atoms in their aliphatic side chain. Adenine dinucleotide analogs of tiazofurin, selenazofurin and benzamide riboside were synthesized as P1, P2-disubstituted pyrophosphates. Cytotoxicity of each analog was examined in human colon adenocarcinoma HT-29 and erythroleukemia K562 cells, and induction of differentiation in K562 cells by these agents was determined. Mycophenolic acid is currently used as an immunosuppressant but its anticancer action is limited by inactivation due to rapid glucuronidation. The new analogs show resistance to metabolism to inactive species and exhibit enhanced cytotoxicity in tumor cell lines, and therefore could be useful as anticancer agents.

Original languageEnglish
Pages (from-to)31-38
Number of pages8
JournalCancer Letters
Volume181
Issue number1
DOIs
StatePublished - Jul 8 2002

Fingerprint

tiazofurin
Mycophenolic Acid
Organophosphonates
IMP Dehydrogenase
Cell Line
K562 Cells
Adenosine
Neoplasms
Leukemia, Erythroblastic, Acute
Niacinamide
Diphosphates
Immunosuppressive Agents
Tumor Cell Line
Antineoplastic Agents
NAD
Cell Differentiation
Colon
Adenocarcinoma
Carbon
Alcohols

Keywords

  • Cancer chemotherapy
  • Cytotoxicity
  • Differentiation
  • Mycophenolic acid

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology
  • Oncology

Cite this

Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines. / Yalowitz, Joel A.; Pankiewicz, Krzysztof; Patterson, Steven E.; Jayaram, Hiremagalur N.

In: Cancer Letters, Vol. 181, No. 1, 08.07.2002, p. 31-38.

Research output: Contribution to journalArticle

Yalowitz, Joel A. ; Pankiewicz, Krzysztof ; Patterson, Steven E. ; Jayaram, Hiremagalur N. / Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines. In: Cancer Letters. 2002 ; Vol. 181, No. 1. pp. 31-38.
@article{283bebff1d3c404f8b7dbd225aee6fca,
title = "Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines",
abstract = "Mycophenolic acid (MPA) is a fungally-derived inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH). MPA binds IMPDH at the nicotinamide sub-site of the NAD cofactor binding domain leaving the adenosine sub-site empty. In order to improve the binding affinity we synthesized MPA analogs by linking adenosine 5′-methylenebis(phosphonate) with mycophenolic alcohols containing 2-, 4-, and 6-carbon atoms in their aliphatic side chain. Adenine dinucleotide analogs of tiazofurin, selenazofurin and benzamide riboside were synthesized as P1, P2-disubstituted pyrophosphates. Cytotoxicity of each analog was examined in human colon adenocarcinoma HT-29 and erythroleukemia K562 cells, and induction of differentiation in K562 cells by these agents was determined. Mycophenolic acid is currently used as an immunosuppressant but its anticancer action is limited by inactivation due to rapid glucuronidation. The new analogs show resistance to metabolism to inactive species and exhibit enhanced cytotoxicity in tumor cell lines, and therefore could be useful as anticancer agents.",
keywords = "Cancer chemotherapy, Cytotoxicity, Differentiation, Mycophenolic acid",
author = "Yalowitz, {Joel A.} and Krzysztof Pankiewicz and Patterson, {Steven E.} and Jayaram, {Hiremagalur N.}",
year = "2002",
month = "7",
day = "8",
doi = "10.1016/S0304-3835(02)00045-9",
language = "English",
volume = "181",
pages = "31--38",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines

AU - Yalowitz, Joel A.

AU - Pankiewicz, Krzysztof

AU - Patterson, Steven E.

AU - Jayaram, Hiremagalur N.

PY - 2002/7/8

Y1 - 2002/7/8

N2 - Mycophenolic acid (MPA) is a fungally-derived inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH). MPA binds IMPDH at the nicotinamide sub-site of the NAD cofactor binding domain leaving the adenosine sub-site empty. In order to improve the binding affinity we synthesized MPA analogs by linking adenosine 5′-methylenebis(phosphonate) with mycophenolic alcohols containing 2-, 4-, and 6-carbon atoms in their aliphatic side chain. Adenine dinucleotide analogs of tiazofurin, selenazofurin and benzamide riboside were synthesized as P1, P2-disubstituted pyrophosphates. Cytotoxicity of each analog was examined in human colon adenocarcinoma HT-29 and erythroleukemia K562 cells, and induction of differentiation in K562 cells by these agents was determined. Mycophenolic acid is currently used as an immunosuppressant but its anticancer action is limited by inactivation due to rapid glucuronidation. The new analogs show resistance to metabolism to inactive species and exhibit enhanced cytotoxicity in tumor cell lines, and therefore could be useful as anticancer agents.

AB - Mycophenolic acid (MPA) is a fungally-derived inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH). MPA binds IMPDH at the nicotinamide sub-site of the NAD cofactor binding domain leaving the adenosine sub-site empty. In order to improve the binding affinity we synthesized MPA analogs by linking adenosine 5′-methylenebis(phosphonate) with mycophenolic alcohols containing 2-, 4-, and 6-carbon atoms in their aliphatic side chain. Adenine dinucleotide analogs of tiazofurin, selenazofurin and benzamide riboside were synthesized as P1, P2-disubstituted pyrophosphates. Cytotoxicity of each analog was examined in human colon adenocarcinoma HT-29 and erythroleukemia K562 cells, and induction of differentiation in K562 cells by these agents was determined. Mycophenolic acid is currently used as an immunosuppressant but its anticancer action is limited by inactivation due to rapid glucuronidation. The new analogs show resistance to metabolism to inactive species and exhibit enhanced cytotoxicity in tumor cell lines, and therefore could be useful as anticancer agents.

KW - Cancer chemotherapy

KW - Cytotoxicity

KW - Differentiation

KW - Mycophenolic acid

UR - http://www.scopus.com/inward/record.url?scp=0037043129&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037043129&partnerID=8YFLogxK

U2 - 10.1016/S0304-3835(02)00045-9

DO - 10.1016/S0304-3835(02)00045-9

M3 - Article

C2 - 12430176

AN - SCOPUS:0037043129

VL - 181

SP - 31

EP - 38

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

IS - 1

ER -