No abstract

HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a Ki value of 2.2 nM and a submicromolar EC50 in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 Å resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3 subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition. rational drug design ͉ aspartic proteases ͉ carboranes ͉ x-ray structure analysis ͉ virostatics

Synthesis of various compounds containing the l-carba-c1oso-dodecaborane cage is reported. The isolated derivatives include zwitterionic I-L-I-CBlt Htl (L = H3N and (CH3hS) and 12-L-I-CB tt Htl (L = (CH3)2S and CH 3 SCH 2 SCH 3 ) compounds along with C-substituted derivatives of the general formula [I-X-CBII HI tl-(X = HOOC, HO, CH 3 0, HS and CH 3 S).Direct halogenation of [1-CB II H I2 1-produces [7,8,9,1O,12-CI s -I-CB II H 7 1-, [7,8,9,10,11,12--X6-I-CBIIH61-(X = CI, Br), [12-1-CB II H I tl-and [7,12-I 2 +CB II H I0 1-substituted species. Constitution of all produ(ts was established by t H, liB, IR and mass spectrometry and is supported by some chemical reactions of the compounds.The [1-CBl.lH12]-anion (I) was first isolated in 1967 by Knoth!, who later 2 improved the synthesis and made initial attempts at substitution, impure samples of B-bromo and 1-(CH 3 hSi-derivatives being the only products. We have recently found a more convenient route 3 .4 to the parent anion I and to some of its uncharged l-L-I-CBllHll (II) (L = CH3NH 2, (CH3)2NH and (CH3hN) congeners. We wish to report in this paper some other possibilities of synthetizing a series of new substituted derivatives in this area of borane chemistry.Several new derivatives of the anion I and its zwitterionic analogues II can be obtained either from the relevant 7-substituted 7-carba-nido-undecaboranes, 7-L-7--CBlOHI2 (III), by inserting the missing boron vertex or by modifying the present exoskeletal functional group in the compounds of the type II.If 7-H3N-7-CBlOHI2 (IlIa) is treated with sodium tetrahydroborate followed by prolonged heating with triethylamine borane at 200°C and the intermediate product is then hydrolyzed with hydrochloric acid, l-amine-l-carba-closo-dodecaborane(ll), I-H3N-I-CBuHu (lIa), can be obtained in good yield as the parent compound of the loN-substituted species. Its N-monomethylderivative lIb is available from the N,N-dimethyl derivative 3 lIe by a curious demethylation with iodine 4 and the N,N,N-trimethyl derivative lId results from successive methylation of any of compounds 11 a-e. Derivatives II a -e behave as weak N-acids with pK" values 6'0, 6'5, and 5'7, respectively (50% ethanol), giving rise to anions [1-H 2N-I-CB IIH II] -(Ia). [1-CH3NH-I-CB1.1HII]-(Ib)4 and [1-(CH3)2N-I-CBtIHu]-(Ie)3.

Treatment of 7-(CH3)3N-7-CB10H12 with triethylamineborane(3) at 180-200 °C proceeds under splitting off one methyl group and inserting one boron vertex to obtain 1-(CH3)2NH-1-CB11H11. Methylation of the latter compound produces 1-(CH3)3N-1-CB11H11 which can be reduced to the parent 1-CB11H12- anion with sodium in liquid ammonia. The constitution of all compounds was established by NMR and mass spectroscopy.