Boronated protohaemins: synthesis and in vivo antitumour efficacy.
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(-1) 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.
Ol'shevskaya
Valentina A
VA
A. N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilov Street, 119991 Moscow, Russia. olshevsk@ineos.ac.ru
Nikitina
Roza G
RG
Zaitsev
Andrei V
AV
Luzgina
Valentina N
VN
Kononova
Elena G
EG
Morozova
Tamila G
TG
Drozhzhina
Valentina V
VV
Ivanov
Oleg G
OG
Kaplan
Mikhail A
MA
Kalinin
Valery N
VN
Shtil
Alexander A
AA
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006427:Hemin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010778:Photochemotherapy; D051381:Rats
D000970:Antineoplastic Agents; D001896:Boron Compounds; D006427:Hemin