Hypoxia-selective agents: radiosensitisers and cytotoxins

Jenkins, Terence C.

doi:10.1007/978-94-009-0397-5_13

Cited by 5 publications

(3 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other metalloporphyrins were non-toxic under oxic or hypoxic conditions. The cationic Co(Ill) porphyrins almost certainly have higher reduction potentials than the other tested metalloporphyrins, and the data would then be consistent with the correlation between reduction potentials and toxicity established for a series of nitroimidazoles [10]. The mechanism for the hypoxic selectivity of cobalt(Ill) complexes of aliphatic mustards is considered to involve reduction of the substitution-inert Co(Ill) complexes to the kinetically labile Co(ll) complexes, and then release of the toxic mustard ligands [22].…”

Section: Toxicitysupporting

confidence: 75%

“…It has been reported that nitro groups play a key role for the hypoxic toxicity and radiosensitising activities of nitro-aromatic compounds such as nitroimidazoles, due to their electron affinities [10]. We have introduced the nitro (NO2) group, the nitroso group (-NO) into the porphyrin structures in order to increase the electron affinities, and the positively charged methylpyridinium group to improve solubility properties of the resultant compounds with the expectation that this may lead to better hypoxia selective and radiosensitising agents.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Porphyrins and Metalloporphyrins: Potential Hypoxic Agents

et al. 1996

View full text Add to dashboard Cite

Synthetic water-soluble porphyrins and their metalloporphyrin derivatives with Co(Ill), Cu(ll), Ru(ll) and Pt(ll), containing various functional groups within the meso-positions of the porphyrin, were synthesised and evaluated as hypoxic agents, especially as cytotoxins and radiosensitisers. Cobalt complexes of the porphyrins containing positively charged methylpyridinium groups showed selective toxicity toward hypoxic Chinese Hamster Ovary (CHO) cells. The Co(Ill) complexes of the cationic and the anionic porphyrins are all weak radiosensitisers toward hypoxic cells, the highest sensitisation enhancement ratio (SER 1.22, at 50 #M) being with a porphyrin complex containing a cis-arrangement of two nitro and two methylpyridinium meso-substituents. A copper complex of a tetracationic porphyrin showed slight radiosensitisation activity with an SER value of about 1.1. The other metalloporphyrins showed no hypoxic selectivity or radiosensitisation activity. In total, over 50 porphyrin free bases have been synthesised, of which half are water-soluble and have been metallated; thus, the chemistry is now in place for further development of water-soluble hypoxic agents.

show abstract

Section: Toxicitysupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Porphyrins and Metalloporphyrins: Potential Hypoxic Agents

et al. 1996

View full text Add to dashboard Cite

show abstract

“…However, hypoxia also creates an environment conducive to reductive processes, which results in an important exploitable difference between normal and neoplastic tissues . This observation has led to extensive efforts to design and develop several classes of synthetic nitro-containing hypoxia-selective agents, including analogues of nitroimidazoles (for a review, see ref ), nitroacridines, benzotriazine N -oxides, nitrobenzyl halides and carbamates, , nitrobenzyl mustard quaternary salts, , and nitrobenzyl phosphorodiamidates − to develop prodrugs of this class with preferential toxicity to hypoxic cells of solid tumors relative to their aerobic counterparts.…”

mentioning

confidence: 99%

Hypoxia-Selective Nitrobenzyloxycarbonyl Derivatives of 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines

et al. 1999

View full text Add to dashboard Cite

Some 4- and 2-(nitrobenzyloxycarbonyl)-1, 2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines (4, 6, and 7) were synthesized and evaluated for their ability to exert preferential toxicity to hypoxic EMT6 mammary carcinoma cells using a colony-forming assay. Of these, the 4,5-dimethoxy-2-nitro analogue 6 (50 microM, 1-h exposure) caused greater than 3 logs of kill of hypoxic cells, with relatively minor toxicity to corresponding aerobic cells. The ability of 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues to reach and kill hypoxic cells of solid tumors was also demonstrated using intradermally implanted EMT6 solid tumors in mice. In addition, a possible source of toxicity to normal tissue, i. e., the activation of the 4-nitrobenzyl derivative 4 by glutathione S-transferase-catalyzed thiolysis, was essentially eliminated by replacing one of the benzylic methylene protons by a methyl group. The 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues also appear to be reduced more easily under acidic conditions (pH 6.0) than under neutral conditions, as measured by differential pulse polarography. Since the pH in hypoxic regions is often lower than that in adjacent aerobic regions, this property should aid in the cytotoxic action of these agents against hypoxic cells of solid tumors.

show abstract