Structure-activity Relationships in the Development of Hypoxic Cell Radiosensitizers

Abstract

The efficiency of 35 nitroaromatic and nitroheterocyclic compounds in radiosensitizing hypoxic Chinese Hamster cells in vitro was determined. The concentration C of the compound required to achieve an enhancement ratio of 1.6 was measured, and the redox and partition properties were quantified as the one-electron reduction potential at pH 7, E, and the octanol: water partition coefficient, P, respectively. Most of the compounds studied were 2-nitroimidazoles, but some 4- and 5-nitromidazoles, 5-nitrofurans and nitrobenzenes were investigated for comparison. Together with data for nine nitroimidazoles previously reported, the results were fitted to a structure-activity relationship of the form -log C = b0 + b1E + b2 log P + b3 (log P)2 using multiple linear regression analysis. Statistical tests showed that the coefficients b2 and b3 were not significantly different from zero and the simpler equation, obtained by omitting the terms in log P, explained 85 per cent of the variance in log C. Earlier reports that the radiosensitization efficiency of nitro compounds in vitro largely depends on the reduction potential were confirmed. The conclusive demonstration that P is unimportant in vitro is valuable in interpreting the results of experiments in vivo, where P is expected to have a much greater influence on biological response.

Porphyrin chemistry pertaining to the design of anti-cancer drugs; part 1, the synthesis of porphyrins containing meso-pyridyl and meso-substituted phenyl functional groups

“…andTetPyP (6), with phenyl and (or) pyridyl meso substituents, were synthesized from condensation of pyrrole, benzaldehyde, and 4-pyridinecarboxaldehyde (2:l:l) as described generally by Little et al (12). Benzaldehyde (3.0 mL), 4-pyridinecarboxaldehyde (4.0 mL), and pyrrole (4.4 mL) were added to hot propionic acid (250 mL) in a 500 mL round-bottom flask, and the mixture was refluxed for 1 h. A precipitate (0.55 g) was filtered off from the cooled reaction mixture.…”

“…Porphyrin drugs used in photodynamic therapy (PDT) have good selectivity toward tumors because of accumulation in cancer cells, but the therapy has a limitation governed by tissue penetration of the light (2). The rationale for the work described here was that the radiosensitization abilities of porphyrins (3)(4)(5) might be improved by introduction of certain groups (including nitro groups and metal ions, which have been shown in non-porphyrin systems to act as radiosensitizers (6)), with the tumor accumulation abilities being retained or improved, possibly by balancing lipophilicity and hydrophilicity of the porphyrin or by introducing nitro group(s) (6). Use of such a drug, which first accumulates in tumors, then kill cells via sensitization of the cells to ionizing radiation, may overcome the noted limitations of both radiotherapy and PDT because hypoxic cells might be selectively sensitized and X-rays are known to penetrate tissues well.…”

Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

“…Furthermore, it has long been known that the correlation between electron affinity and efficacy of a radiosensitizer is subject to modulation by a number of other molecular factors, so that reduction potentials should be used as a no more than a guide to selecting promising hypoxia-selective agents [106][107][108].…”

Synthetic Nitroimidazoles: Biological Activities and Mutagenicity Relationships

“…Furthermore, 5-nitro-substituted haloimidazoles, showed important biological activity as potential radiosensitizers [93] and other imidazole derivatives having 5-alkylsulfanyl residues exhibited remarkable antitumor activity [94].…”