Synthesis, comparative photosensitizing efficacy, human serum albumin (site II) binding ability, and intracellular localization characteristics of novel benzobacteriochlorins derived from vic-dihydroxybacteriochlorins.

Abstract

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 vic-dihydroxybacteriochlorins. The 8-vinylchlorins 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 micromol/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 (3)H-PK11195 (PBR probe, (3)H-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.

• Authors: Guolin Li, Andrew Graham, Yihui Chen, Mahabeer P Dobhal, Janet Morgan, Gang Zheng, Andrei Kozyrev, Allan Oseroff, Thomas J Dougherty, Ravindra K Pandey
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 46 Issue 25 Pg. 5349-59 (Dec 04 2003) ISSN: 0022-2623 [Print] United States
• PMID: 14640543 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Photosensitizing Agents
• Receptors, GABA-A
• Serum Albumin
• Chlorophyll
• Chlorophyll A

Topics

• Animals
• Binding Sites
• Binding, Competitive
• Cell Survival (drug effects)
• Chlorophyll (chemistry)
• Chlorophyll A
• Drug Screening Assays, Antitumor
• Humans
• Mice
• Mice, Inbred C3H
• Mitochondria (metabolism)
• Neoplasm Transplantation
• Photochemotherapy
• Photosensitizing Agents (chemical synthesis, chemistry, pharmacology, toxicity)
• Protein Binding
• Radioligand Assay
• Receptors, GABA-A (metabolism)
• Serum Albumin (chemistry)
• Skin (drug effects)
• Spectrophotometry
• Structure-Activity Relationship
• Tumor Cells, Cultured