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Boronated protohaemins: Synthesis and in vivo antitumour efficacy

Organic and Biomolecular Chemistry, ISSN: 1477-0520, Vol: 4, Issue: 20, Page: 3815-3821
2006
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Article Description

The conjugates of porphyrin macrocycles with boron-containing polyhedra are under investigation as agents for binary treatment strategies of cancer. Aiming at the design of photoactive compounds with low-to-zero dark toxicity, we synthesized a series of carboranyl and monocarbon-carboranyl derivatives of protohaemin IX using the activation of porphyrin carboxylic groups with di-tert-butyl pyrocarbonate or pivaloyl chloride. The water-soluble 1,3,5,8-tetramethyl-2,4-divinyl-6(7)-[2′-(closo-monocarbon-carborane- 1″-yl)methoxycarbonylethyl]-7(6)-(2′-carboxyethyl)porphyrin Fe(iii) (compound 9) exerted no discernible cytotoxicity for cultured mammalian cells, nor did it cause general toxicity in rats. Importantly, 9 demonstrated dose-dependent activity as a phototoxin in photodynamic therapy of M-1 sarcoma-bearing rats. In animals injected with 20 mg kg of 9, the tumours shrank by day 3 after one single irradiation of the tumour with red laser light. Between 7 and 14 days post-irradiation, 88.9% of rats were tumour-free; no recurrence of the disease was detectable within at least 90 days. Protohaemin IX alone was without effect, indicating that boronation is important for the phototoxic activity of 9. This is the first study that presents the synthesis and preclinical in vivo efficacy of boronated derivatives of protohaemin as phototoxins. The applicability in photodynamic treatment broadens the therapeutic potential of boronated porphyrins beyond their conventional role as radiosensitizers in boron neutron capture therapy. © The Royal Society of Chemistry 2006.

Bibliographic Details

Valentina A. Ol'shevskaya; Andrei V. Zaitsev; Elena G. Kononova; Valery N. Kalinin; Roza G. Nikitina; Tamila G. Morozova; Valentina V. Drozhzhina; Mikhail A. Kaplan; Valentina N. Luzgina; Oleg G. Ivanov; Alexander A. Shtil

Royal Society of Chemistry (RSC)

Biochemistry, Genetics and Molecular Biology; Chemistry

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