Novel Boron-Containing, Nonclassical Antifolates:  Synthesis and Preliminary Biological and Structural Evaluation

Abstract

Two boron-containing, ortho-icosahedral carborane lipophilic antifolates were synthesized, and the crystal structures of their ternary complexes with human dihydrofolate reductase (DHFR) and dihydronicotinamide adenine dinucleotide phosphate were determined. The compounds were screened for activity against DHFR from six sources (human, rat liver, Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and Lactobacillus casei) and showed good to modest activity against these enzymes. The compounds were also tested for antibacterial activity against L. casei, M. tuberculosis H37Ra, and three M. avium strains and for cytotoxic activity against seven different human tumor cell lines. Antibacterial and cytotoxic activity was modest, with one sample, the closo-carborane 4, showing about 10-fold greater activity. The less toxic nido-carborane 2 was also tested as a candidate for boron neutron capture therapy, but showed poor tumor retention and low selectivity ratios for boron distribution in tumor tissue versus normal tissue.

New strategy of efficient inhibition of cancer cells by carborane carboxylic acid–CdTe nanocomposites

“…19 As an important pharmacophore, the three-dimensional carborane cage shares approximately the same volume as a rotating phenyl ring, which makes it a candidate for bioisosteric replacements of phenyl rings as rigid scaffolding in bioactive molecules and pharmacological agents. A myriad of boronated derivatives of amino acids and peptides, 20 estrogen receptor modulators, 21 androgen antagonists, 22 and others 23,24 have displayed comparable or even superior biological activities to those of the nonboronated counterparts. Numerous carborane complexes have been synthesized and found to show potential anticancer activity.…”

In Silico Carborane Docking to Proteins and Potential Drug Targets

“…87,88 The use of carborane derivative as dihydrofolate reductase was discussed in the past. 32 vi. Antibodies.…”

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“…Various nitrogen heterocycles, 6-8 boron containing carboranes 9 and a tripeptide compound have been reported as Mtb DHFR inhibitors. 10 Our research group has been actively involved in the synthesis of several novel, diverse inhibitors of DHFR for Mtb 11,12 and opportunistic pathogens, [13][14][15] including Mycobacterium avium.…”