PubMed · 12774797
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2003-05-09. [Decrease of HIV-1 virus load by nevirapin/efavirenz].. https://pubmed.ncbi.nlm.nih.gov/12774797/
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Monte Carlo-extended linear response (MC/ELR) calculations are used to examine the binding of efavirenz analogues with the K103N mutant of HIV-1 reverse transcriptase (HIVRT). A regression equation previously reported for the wild type (WT) enzyme is shown to predict 47 experimental activities for the K103N mutant with a q(2)=0.55 and avg error of only 0.46 kcal/mol. Further analysis identifies the key features for binding to the K103N mutant: ligand flexibility, burial of hydrophobic surface area, and protein-ligand van der Waals interactions.
We have synthesized the nickel(II) 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins with -Br (2a) or -I (2b) at the alkyne termini position from the corresponding 2,3-diethynyl analogue (1). The cross coupling of nickel(II) 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with trimethyl(trimethylstannanylethynyl)silane in the presence of a Pd0 catalyst and subsequent deprotection with base under aqueous conditions yields the nickel(II) 2,3-diethynyl-5,10,15,20-tetraphenylporphyrin (1). Subsequent reaction of 1 with N-bromo- or N-iodosuccinimide in dry acetone in the presence of AgNO3 yields 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins in 70% (2a) and 68% (2b) yields. The X-ray crystal structures of 2a,b show that the porphyrin backbone deviates significantly from planarity due to a Ni(II)-induced mixture of the classic ruffle and saddle distortions. Thermolysis of 2a at 190 degrees C for 6 h in chlorobenzene and 30-fold 1,4-cyclohexadiene (CHD) generates the Bergman cyclized nickel(II) dibromopicenoporphyrin product (3) in 65% yield, which derives from diradical addition across the adjacent meso-phenyl substituents. Similarly, nickel(II) 2,3-bis(iodoethynyl)-5,10,15,20-tetraphenylporphyrin, 2b, cyclizes at 190 degrees C in chlorobenzene/CHD via high-temperature substitution of iodine by hydrogen (from CHD) or chlorine (from solvent) to afford a mixture of 4 (15%) and 5 (45%). Remarkably, ambient temperature incubation of 2a in MeOH/CHCl3 (1:3, 22 h) or chlorobenzene/CHD (3:1, 24 h) leads to generation of 3 in 15% and 22% isolated yields, respectively. Addition of 1.2 equiv of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in CHCl3/MeOH dramatically accelerates the rate of reaction, producing 3 in 30% yield within 0.5 h. The origin of the ambient temperature activation of 2a derives from the ability of electron-withdrawing functionalities at the alkyne termini to decrease the activation barrier to the Bergman product.
The cycloisomerization of diyne-ols catalyzed by [CpRu(CH3CN)3]PF6 to 2-vinyl-1-acylcycloalkenes proceeds via a ruthenacyclopentadiene involving initial ionization of the tertiary or secondary alcohol, followed by readdition. In the case of primary alcohols, a competing pathway wherein water first adds would appear to occur. The feasibility of this proposed minor pathway was tested in the reaction of diynes in the presence of water. Quite excitingly, cyclization comcommittant with addition of water to form 1-acylcycloalkenes occurs. This proves to be general process to form five- and six-membered rings. Interestingly, hydrative cyclization of Z-5-decen-2,8-diyne to 1-acetyl-2-ethyl-cyclohexa-1,4-diene occurs without isomerization of the double bonds. Furthermore, the epoxide of the same substrate cyclizes without opening of the strained epoxide. Unsymmetrically substituted diynes cyclize with remarkable chemoselectivity wherein water attacks the less hindered alkynes. beta-branching of any kind gives only a single product. Remarkably, even competing methyl versus ethyl still effects a 2.5:1 selectivity in favoring water addition to the methyl-bearing alkyne. Alcohols can replace water and provide enol ethers. Strong mechanistic evidence suggests two reaction manifolds indeed operate, depending upon the presence of propargyl alcohols and the degree of substitution on the hydroxyl-bearing carbon.