Quadruplex-Interactive Agents as Telomerase Inhibitors:  Synthesis of Porphyrins and Structure−Activity Relationship for the Inhibition of Telomerase

• Published in: Journal of medicinal chemistry Vol. 44; no. 26; pp. 4509 - 4523
• Main Authors: Shi, Dong-Fang, Wheelhouse, Richard T, Sun, Daekyu, Hurley, Laurence H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.12.2001; Amer Chemical Soc
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell-Free System; Chemistry, Medicinal; DNA - chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; G-Quadruplexes; General aspects; HeLa Cells; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Porphyrins - chemical synthesis; Porphyrins - chemistry; Porphyrins - pharmacology; Pyridines - chemistry; Pyrroles - chemistry; Science & Technology; Structure-Activity Relationship; Telomerase - antagonists & inhibitors; PYRROLIC COMPOUNDS; TARGET; CATIONIC PORPHYRINS; FRAGILITY; DNA; CHEMISTRY; SEPARATION; IDENTIFICATION; BINDING; DERIVATIVES; Antineoplastic agent; Pentacyclic compound; Human; Organic cation; Enzyme; Nitrogen heterocycle; Iminium compounds; Benzene derivatives; Enzyme inhibitor; Molecular interaction; In vitro; Modeling; Telomere; Tetrad; Macrocycle; Pyridine derivatives; Biological fixation; Structure activity relation; Molecular model; Aromatic compound; Mechanism of action; Chemical synthesis; Telomerase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010246u

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.