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March 2002
Vol. 5, No. 3, p 12.
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Teasing telomerase inhibitors

Porphyrin telomerase inhibitor TMPyP4.
Porphyrin telomerase inhibitor TMPyP4.
In recent years, much has been made of the role of telomeres—chromosome ends—in cellular longevity and cancer. Telomeres contain regions of single-stranded DNA that are rich in guanosine (G) and fold back on themselves to form a structure of near-planar, hydrogen-bonded G-tetrads. As a cell ages, telomeres shorten with each replication, and when they are lost, chromosomal damage leads to cell death.

Telomerase is an enzyme that can restore telomeres, is typically turned off in normal cells, and is expressed in only a few specialized cell lines. The enzyme, however, is expressed in more than 90% of tumor cell lines. It is thought that by maintaining the telomeres of tumor cell chromosomes, the telomerase promotes the rampant growth and immortality of these cells. Thus, compounds that inhibit telomerase activity are potentially powerful anticancer drugs.

Although some researchers have targeted the telomerase enzyme for drug development, others have focused their efforts on compounds that target its DNA substrate. The latter group can be divided into two types: the putative quadruplex groove binders such as the carbocyanine dyes and the extended planar aromatic chromophores that intercalate with the G-tetrads. One member of the latter type is the cationic 5,10,15,20-tetra(N-methyl-4-pyridyl)porphyrin (TMPyP4), which has been extensively studied by Laurence Hurley from the University of Texas (Austin) and his colleagues from various institutions.

Recently, Hurley’s group generated a series of TMPyP4 analogues, adjusting the coordinating metal ions, making substitutions in the pyrrole rings, and modifying the substituent and cationic side groups; then they assayed the analogues for telomerase inhibition using a cell-free system (J. Med. Chem. 2001, 44 (26), 4509–4523). They found several compounds that showed notable inhibition, but what is perhaps more important is that they discerned the following structure–activity relationship rules:

  • the porphyrin face must be available for stacking,
  • cationic side groups are important for inhibitor function but can be interchanged and combined with hydrogen-bonding groups, and
  • substitutions are tolerated only at the porphyrin meso positions, and the size of these substitutions should match the size of the grooves in which they lie.

Hurley and his group believe that these basic rules will provide a firm foundation for the future development of telomerase-inhibiting drugs.


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