Boron-Containing Heterocycles:  Syntheses, Structures, and Properties of Benzoborauracils and a Benzoborauracil Nucleoside

Abstract

Benzo-fused boron-containing heterocycles (benzoborauracils), 1-hydroxy-1H-2,4,1-benzodiazaborin-3-one (3a), 1-hydroxy-2-methyl-1H-2,4,1-benzodiazaborin-3-one (3b), and 1-hydroxy-2-phenyl-1H-2,4,1-benzodiazaborin-3-one (3c) were synthesized, and their structures were established on the basis of 1H, 13C, and 11B NMR spectroscopies, mass spectrometry, and microelemental analyses. The structures of compounds 3b and 3c were unambiguously confirmed by X-ray crystallographic analyses. 11B NMR spectral analyses of the methanolic solutions of benzoborauracils 3a−c confirmed the formation of the corresponding bis-methanol adducts 13a−c. The structure of the N-Ph bis-methanol adduct 13c was confirmed by X-ray crystallography. The stabilities of these bis-methanol adducts depend on the substituent at the N2 position of 3a−c. The bis-methanol adducts are readily reconverted to the corresponding benzoborauracils upon removal of methanol. The first stable benzoborauracil nucleoside, 4-[5-O-(tert-butyldimethylsilyl)-2,3-O-disopropylidene-α-d-ribofuranosyl]-1-hydroxy-2-methyl-1H-2,4,1-benzodiazaborin-3-one (25) was prepared in two steps by treatment of 2-aminophenylboronic acid with 5-O-(tert-butyldimethylsilyl)-2,3-O-diisopropylidene-d-ribofuranose followed by its reaction with methylisocyanate.

Towards carborane-functionalised structures for the treatment of brain cancer

“…In parallel, quinazolines, which may be regarded as hydrophobic analogues of pyrimidines, are known to display high affinity for the nucleic acids present in tumour cells [102]. Zhou et al [103] have shown that hydrolytic stability is influenced by the number of hydroxyl-boryl groups in the molecular structure and that the biochemical properties of such compounds are highly sensitive to the presence of bulky aromatic groups. On the basis of this work it has been proposed that the carborane cage may be preferentially linked to the quinazoline group via a thioester linker [104].…”

Novel glycosylated carboranylquinazolines for boron neutron capture therapy of tumors: synthesis, characterization, and in vitro toxicity studies

“…These species offer the advantages of high boron content (17-27% boron by weight), water solubility and very low cellular toxicity compared to the previously boronated quinazolines. [18] The compounds were synthesized in acceptable yields from readily available starting materials. The reactions as well as workup procedures and the purifications for all products were readily feasible.…”

“…Initial approaches for its use in BNCT were concentrated on the synthesis of benzofused boronated pyrimidine derivatives. [17,18] In this case only one boron atom was placed within the pyrimidine nucleus and flanked by two nitrogen atoms. However, these compounds were found to be hydrolytically and biologically unstable, and they failed to become incorporated selectively into tumor cells or into nucleic acids.…”

“…Moreover, the standard glycosylation procedures on these compounds failed to produce the required nucleosides. [18] The rotational for choosing a carborane cage as the boron containing moiety was the 10-fold increase in boron content compared with above mentioned groups which contain just one boron atom. In addition, there is an increased lipophilicity due to the carborane moiety, which could aid cellular penetration.…”

“…Our objective was to incorporate a carboranyl moiety into N-glycosylaminoquinazolines. The rationale was that such structures would possess: (1) a 10-fold increase in boron content compared with the previously prepared boronated quinazolines; [17,18] and (2) enhanced membrane penetration due to the presence of hydrophilic (sugar) and hydrophobic (carborane) parts in the compounds; additionally, (3) quinazolin-4(3H)-ones have different binding modes with DNA and therefore, N-glycosyl carboranylquinazolines may be able to target DNA directly once they penetrate the cell membrane. Additionally, the results of in vitro studies are presented to evaluate the preliminary application of the new N-glycosyl carboranylquinazolines for cancer treatment by BNCT.…”