Four novel linear non‐peptidic HIV‐1 protease inhibitors derived from 2,5‐diamino‐1,6‐diphenyl‐3‐hexanol were synthesized and characterized. All of them exhibit tight binding to HIV‐1 protease, with inhibition constants Ki in the range 20 pm–5 nm. The investigated inhibitors were crystallized, and their crystal structures were determined by X‐ray diffraction. In all cases, the conformations found in the crystalline state differ significantly from the conformations obtained by computational docking of the inhibitor in the binding cleft of native HIV‐1 protease. Owing to the prevalence of hydrophobic substituents in all these inhibitors, the conformational mobility in water solution is restricted to their compact forms. The spectrum of low‐energy conformations in solution dramatically changes during the formation of inhibitor crystals (phenyl ring stacking as a leading motif) or during the formation of a complex with HIV‐1 protease (elongated conformation suitable to fit the enzyme pockets as a factor responsible for tight binding). High conformational flexibility and low conformational stress in the molecules of these inhibitors most likely increase their biological activity in comparison with more rigid compounds.

We describe the de novo structure-based design of C2 symmetric, non-peptidic HIV PR inhibitors. Cyclic ureas were chosen as synthetic targets owing to their ability to mimic key interacting elements observed in known HIV PP/inhibitor complexes. The urea carbonyl oxygen serves as a replacement for the buried, structural water that occurs in peptide-based inhibitor complexes. The conformational analysis of the six-membered pyrimidone ring suggests that N-substituted derivatives should exhibit a marked stereochemical preference for binding.

Two new potent allosteric effectors of hemoglobin, RSR-4 [2-[4-[[(3,5-dichloroanilino)carbonyl]-methyl]phenoxy]-2- methylpropionic acid] and RSR-13 [2-[4-[[(3,5-dimethlanilino)carbonyl]methyl]-phenoxy]-2-methylp rop ionic, are compared to the previously reported compounds L3,5 and L3,4,5 [Lalezari, I., Lalezari, P., Poyart, C., Marden, M., Kister, J., Bohn, B., Fermi, G., & Perutz, M. F. (1990) Biochemistry 29, 1515]. Unlike L3,5 and L3,4,5, RSR-4 and RSR-13 are less impeded by physiological concentrations of serum albumin. RSR-4 has also been shown to be more effective than L3,5 in shifting the allosteric equilibrium of bovine Hb toward the low-affinity T-state. X-ray crystal studies show that both RSR-4 and RSR-13 bind to only one pair of symmetry-related sites in the Hb central water cavity whereas previous studies on L3,5 and L3,4,5 demonstrated a second pair of symmetry-related binding sites near Arg 104 beta. Three major interactions between these allosteric effectors and Hb include the acid group with the guanidinium group of C-terminal Arg 141 alpha, the effector's amide oxygen with the ammonium ion of Lys 99 alpha, and the phi electrons of the halogenated or methylated aromatic ring and Asn 108 beta. No explanation has been found for the difference in number of binding sites observed for RSR-4 and RSR-13 (two sites) compared to L3,5 and L3,4,5 (four sites); also no correlation has been made between the number of binding sites and degree of allosteric shift in the oxygen equilibrium curve.(ABSTRACT TRUNCATED AT 250 WORDS)

X-ray diffraction difference electron density maps at 3 Å resolution obtained from di and tetra-ligated T-state hemoglobin (Hb) crystals are reported. Crystals isomorphous with native deoxyhemoglobin were obtained from ammonium sulfate solutions incubated with the synthetic allosteric effector RSR-56. RSR-56 binds at two symmetry-related Hb central water cavity sites and each molecule has major interactions with three different subunit side-chains; one effector with Arg141α2 HC3, Lys99α1 G6 and Asn108β1 and the other with the symmetry related residues, Arg141α1 Lys99α2 and Asn108β2. Crystals mounted in a nitrogen filled glove box were di-ligated as previously found with polyethyleneglycol Hb crystals. Crystals mounted in air under a layer of mother liquor were bright red and showed all four heme groups ligated. The difference electron density from the di-ligated crystals showed atomic movements to be restricted to the immediate neighborhood of the heme groups and the allosteric effector. By contrast, the tetra-ligated structure showed extended difference electron density near amino acid residues around both α and β heme groups and along the α1β2 interface. Ligation of the β heme group appears to magnify the difference density around the α heme groups. There is no evidence of breakage of the Bohr salt bridge, His146β HC3 → Asp94β FG1, in the crystal. The observed difference electron density maps may help to clarify the way the allosteric mechanism is triggered.

Preparation of B-isoprenyldialkylboranes is achieved by adopting the Brandsma modification of the Schlosser procedure, namely metallation of isoprene with potassium 2,2,5,5-tetramethylpiperidide followed by sequential treatment with B-methoxydialkylborane and boron trifluoride-etherate. These reagents are used for the convenient isoprenylation of aldehydes. Reaction of isovaleraldehyde and β, β-dimethylacrolein with B2'isoprenyldiisopinocampheylborane provides both ipsenol and ipsdienol, respectively in 65% yields and 96% ee.

B-2′-Isoprenyldiisopinocampheylborane is prepared by metallation of isoprene with potassium 2,2,5,5-tetramethylpiperidide followed by sequential treatment with B-methoxydiisopinocampheylborane and boron trifluoride-etherate. Condensation of this reagent with aldehydes provides isoprenylated chiral alcohols. This methodology is utilized for an efficient one-pot synthesis of both enantiomers of the pheromones of the bark beetle Ips paraconfusus Lanier, ipsenol and ipsdienol in 96% ee and 65% isolated yields.

AbstractThe title reagent (V) ‐ prepared in three steps via hydroboration of (+)‐2‐carene (I) ‐ is shown to undergo asymmetric allylboration with a variety of aldehydes such as (VI) to give the corresponding homoallylic alcohols in 94‐99% e.e.

AbstractUsing the boranes (I) and (IV) the asym.

The asymmetric crotylboration of representative aldehydes, RCHO (R = Me, Et-), with B-[Z and E ]-crotylbis(2-isocaranyl)boranes (4 and 5 ) proceeds with remarkably high enantioselectivity (>94-98% ee) and diastereoselectivity (>99% de) at -78°C in ethyl ether.