Radioprotective efficacy and toxicity of a new family of aminothiol analogs.
OBJECTIVE
A family of 17 new nucleophilic-polyamine and aminothiol structures was designed and synthesized to identify new topical or systemic radioprotectors with acceptable mammalian toxicity profiles. design elements included: (i) Length and charge of the DNA-interacting, alkylamine backbone, (ii) nucleophilicity of the reactive oxygen species (ROS)-scavenging group, and (iii) non-toxic drug concentration achievable in animal tissues.


METHODS
Mouse maximum tolerated doses (MTD) were determined by increasing intraperitoneal (IP) doses. To assess radioprotective efficacy, mice received IP 0.5 MTD doses prior to an LD95 radiation dose (8.63 Gy), and survival was monitored. Topically applied aminothiol was also scored for prevention of radiation-induced dermatitis (17.3 Gy to skin).


RESULTS
The most radioprotective aminothiols had 4-6 carbons and 1-2 amines, and unlike amifostine and its analogs, displayed a terminal thiol from an alkyl side chain that projected the thiol away from the DNA major groove into the environment surrounding the DNA. The five carbon, single thiol, alkylamine, PrC-210, conferred 100% survival to an otherwise 100% lethal dose of whole-body radiation and achieved 100% prevention of Grade 2-3 radiation dermatitis. By mass spectrometry analysis, the one aminothiol that was tested formed mixed disulfides with cysteine and glutathione.


CONCLUSIONS
Multiple, highly radioprotective, aminothiol structures, with acceptable systemic toxicities, were identified.
ProCertus BioPharm, Inc., Madison, WI, USA.
Richard R
RR
Copp
Daniel D
DD
Peebles
Cheryl M
CM
Soref
William E
WE
Fahl
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D020714:Maximum Tolerated Dose; D051379:Mice; D008813:Mice, Inbred ICR; D011836:Radiation Tolerance / Q000187:drug effects*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000633:toxicity*; D011855:Radiodermatitis / Q000209:etiology* / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000633:toxicity*; D015996:Survival Rate; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D011837:Radiation-Protective Agents; D013438:Sulfhydryl Compounds