Boronated protohaemins: synthesis and in vivo antitumour efficacy

Abstract

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.

Boronated derivatives of chlorin e 6 and fluoride-containing porphyrins as penetrating anions: a study using bilayer lipid membranes

“…Dodecaborate [27,28] and monocarborane [29] have the greatest prospects in terms of new drug development, for they are di and monoanions and provide water solubility. Boronated por phyrin [30], chlorin [31], and hemin [32] were found to be more effective photosensitizers both in vitro and in vivo than their predecessors. Compound 1 was previously shown to accumulate in intracellular organelles such as the Golgi apparatus, endoplasmic reticulum, and other membrane compartments [31].…”

Water-soluble carboranyl-phthalocyanines for BNCT. Synthesis, characterization, and in vitro tests of the Zn(ii)-nido-carboranyl-hexylthiophthalocyanine

“…† As a matter of fact, a few water-soluble polyanionic or amphiphilic nido-carboranyl porphyrins have proven to effectively permeate the membrane of tumoral cells without the mediation of a carrier, and to retain both the whole boron content and the photophysical properties of the macrocyclic ring. [15][16][17][18][19] To the best of our knowledge there is only a report, instead, showing that polyanionic boron-containing phthalocyanines can be taken up by cancerous cells. 20 This is most likely due to the paucity of sufficiently watersoluble phthalocyanines bearing highly boronated chemical functions.…”

Design, Synthesis, Selective Recognition Properties and Targeted Drug Delivery Application

“…Intensive research has led to the design and study of many porphyrin conjugates with carborane units, such as porphyrins substituted in their meso-positions 292,343-359 and on the porphyrin core itself, 360 or protoporphyrin IX derivatives such as BOPP (the tetrakis-carborane carboxylate ester of 2,4-bis-(1,2-dihydroxyethyl)deuteroporphyrin IX) (Figures 36-38). [361][362][363][364][365][366][367][368] An interesting result was obtained by Perona et al using BOPP as a radiosensitizer. 369 They found that cancer cells (WRO, follicular cancer cell line) displayed approximately three times higher sensitivity for BNCT than normal control cells.…”