期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 46, 期 25, 页码 5349-5359出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm030341y
关键词
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资金
- NCI NIH HHS [P30CA16056, CA 55791] Funding Source: Medline
In a sequence of reactions, methyl mesopyropheophorbide a, mesochlorin e(6) trimethyl ester, mesochlorin p(6) trimethyl. ester, mesopurpurin-18-N-hexylimide methyl ester, and mesopurpurin-18-N-3,5-bis(trifluoromethyl)benzylimide methyl ester were synthesized from chlorophyll-a. These chlorins on reacting with osmium tetraoxide produced the corresponding via-dihydroxybacteriochlorins. The 8-vinylehlorins obtained by refluxing the related vic-dihydroxybacteriochlorins in o-dichlorobenzene were individually treated with dimethylacetylenedicarboxylate (DMAD) under Diels-Alder reaction conditions. The intermediate adducts on 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) treatment rearranged to the corresponding stable benzobacteriochlorins, exhibiting the longest wavelength absorption in the range of 737 to 805 nm. In preliminary in vitro (RIF tumor cells) and in vivo screening (C3H/HeJ mice bearing RIF tumors), some of these compounds were found to be quite effective. Under similar treatment conditions (drug dose: 5.0 mumol/kg; light dose: 135 J/cm(2), tumors were exposed to light for 30 min at 24 h postinjection), the benzobacteriochlorins containing N-substituted-imide ring system produced enhanced photosensitizing efficacy with limited skin phototoxicity. These compounds were also found to bind to site II of human serum albumin (HSA). However, no correlation between the binding constant values and photosensitizing efficacy was observed. A competitive intracellular localization study of these novel structures with Rhodamine-123 (a mitochondrial probe) indicated their preferential localization in mitochondria, without producing any specific displacement of H-3-PK11195 (PBR probe, H-3-labeled 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide). These results suggest that the mitochondrial peripheral benzodiazepine receptor (PBR) is not the cellular binding site for this class of compounds.
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