Quadruplex-interactive agents as telomerase inhibitors: Synthesis of porphyrins and structure-activity relationship for the inhibition of telomerase

D. F. Shi, R. T. Wheelhouse, Daekyu Sun, Laurence Hurley

Research output: Contribution to journalArticle

225 Citations (Scopus)

Abstract

The cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) binds to quadruplex DNA and is thereby an inhibitor of human telomerase (Wheelhouse et al. J. Am. Chem. Soc. 1998, 120, 3261-3262). Herein the synthesis and telomerase-inhibiting activity of a wide range of analogues of TMPyP4 are reported, from which rules for a structure-activity relationship (SAR) have been discerned: (1) stacking interactions are critical for telomerase inhibition, (2) positively charged substituents are important but may be interchanged and combined with hydrogen-bonding groups, and (3) substitution is tolerated only on the meso positions of the porphyrin ring, and the bulk of the substituents should be matched to the width of the grooves in which they putatively lie. This SAR is consistent with a model presented for the complexation of TMPyP4 with human telomeric quadruplex DNA.

Original languageEnglish (US)
Pages (from-to)4509-4523
Number of pages15
JournalJournal of Medicinal Chemistry
Volume44
Issue number26
DOIs
StatePublished - Dec 20 2001

Fingerprint

Telomerase
Porphyrins
Structure-Activity Relationship
G-Quadruplexes
DNA
Hydrogen Bonding
Complexation
Hydrogen bonds
Substitution reactions
tetra(4-N-methylpyridyl)porphine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{fcb30767cfc84912834e346b73cff9bb,
title = "Quadruplex-interactive agents as telomerase inhibitors: Synthesis of porphyrins and structure-activity relationship for the inhibition of telomerase",
abstract = "The cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) binds to quadruplex DNA and is thereby an inhibitor of human telomerase (Wheelhouse et al. J. Am. Chem. Soc. 1998, 120, 3261-3262). Herein the synthesis and telomerase-inhibiting activity of a wide range of analogues of TMPyP4 are reported, from which rules for a structure-activity relationship (SAR) have been discerned: (1) stacking interactions are critical for telomerase inhibition, (2) positively charged substituents are important but may be interchanged and combined with hydrogen-bonding groups, and (3) substitution is tolerated only on the meso positions of the porphyrin ring, and the bulk of the substituents should be matched to the width of the grooves in which they putatively lie. This SAR is consistent with a model presented for the complexation of TMPyP4 with human telomeric quadruplex DNA.",
author = "Shi, {D. F.} and Wheelhouse, {R. T.} and Daekyu Sun and Laurence Hurley",
year = "2001",
month = "12",
day = "20",
doi = "10.1021/jm010246u",
language = "English (US)",
volume = "44",
pages = "4509--4523",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "26",

}

TY - JOUR

T1 - Quadruplex-interactive agents as telomerase inhibitors

T2 - Synthesis of porphyrins and structure-activity relationship for the inhibition of telomerase

AU - Shi, D. F.

AU - Wheelhouse, R. T.

AU - Sun, Daekyu

AU - Hurley, Laurence

PY - 2001/12/20

Y1 - 2001/12/20

N2 - The cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) binds to quadruplex DNA and is thereby an inhibitor of human telomerase (Wheelhouse et al. J. Am. Chem. Soc. 1998, 120, 3261-3262). Herein the synthesis and telomerase-inhibiting activity of a wide range of analogues of TMPyP4 are reported, from which rules for a structure-activity relationship (SAR) have been discerned: (1) stacking interactions are critical for telomerase inhibition, (2) positively charged substituents are important but may be interchanged and combined with hydrogen-bonding groups, and (3) substitution is tolerated only on the meso positions of the porphyrin ring, and the bulk of the substituents should be matched to the width of the grooves in which they putatively lie. This SAR is consistent with a model presented for the complexation of TMPyP4 with human telomeric quadruplex DNA.

AB - The cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) binds to quadruplex DNA and is thereby an inhibitor of human telomerase (Wheelhouse et al. J. Am. Chem. Soc. 1998, 120, 3261-3262). Herein the synthesis and telomerase-inhibiting activity of a wide range of analogues of TMPyP4 are reported, from which rules for a structure-activity relationship (SAR) have been discerned: (1) stacking interactions are critical for telomerase inhibition, (2) positively charged substituents are important but may be interchanged and combined with hydrogen-bonding groups, and (3) substitution is tolerated only on the meso positions of the porphyrin ring, and the bulk of the substituents should be matched to the width of the grooves in which they putatively lie. This SAR is consistent with a model presented for the complexation of TMPyP4 with human telomeric quadruplex DNA.

UR - http://www.scopus.com/inward/record.url?scp=0035924232&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035924232&partnerID=8YFLogxK

U2 - 10.1021/jm010246u

DO - 10.1021/jm010246u

M3 - Article

C2 - 11741471

AN - SCOPUS:0035924232

VL - 44

SP - 4509

EP - 4523

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 26

ER -