Intestinal absorption and biodistribution of cosalane and its amino acid conjugates: novel anti-HIV agents.

Cosalane and its amino acid conjugates are potent inhibitors of HIV replication. The purpose of this study was to investigate: (1) the pharmacokinetic disposition of the diglycine (GC) and the diaspartic acid (ASPC) conjugates of cosalane in male Sprague-Dawley rats; (2) intestinal absorption of cosalane and its amino acid conjugates using in vitro (small intestinal segments), in situ (closed loop); and (3) biodistribution of GC and its absolute oral bioavailability in rat. Cosalane and its conjugates exhibited biexponential disposition with very long half-lives upon intravenous dosing. However, these compounds failed to permeate the small intestine unless sodium desoxycholate (5-20 mM) was used as an intestinal permeation enhancer. A rank order correlation in terms of permeation enhancement in a descending order is as follows: GC>Cosalane>ASPC. In situ studies revealed that although the bile salt enhanced the permeation of cosalane across the enterocyte, its hepatic uptake was extensive. However, 66% of the absorbed dose of GC escaped uptake by the reticuloendothelial system (RES) and its biodistribution studies showed that the uptake by the RES was significantly lower compared to the parent compound. GC had an absolute oral bioavailability of 5.10+/-1.51%. Therefore, GC appears to be a favorable candidate for further development.

Correlation of anti-HIV activity with anion spacing in a series of cosalane analogues with extended polycarboxylate pharmacophores.

Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6--12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, beta-alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.

Inhibition of RANTES/CCR1-mediated chemotaxis by cosalane and related compounds.

The anti-HIV agent cosalane and several of its analogues inhibited RANTES-induced migration of human monocytes, but they did not inhibit migration induced by MIP1alpha or MIP1beta. RANTES-induced migration of single receptor CCRI-HEK transfectants was also inhibited by the cosalanes. Acetylation of the reactive amino groups of RANTES abrogated the inhibitory activity of cosalane. The data suggest that cosalane and its structural analogues may interfere with the RANTES/CCR1 interaction by binding to RANTES.

Anti-HIV activity of a series of cosalane amino acid conjugates.

The binding of the anti-HIV agent cosalane to CD4 is thought to involve ionic interactions of negatively charged carboxylates of the ligand with positively charged residues on the surface of the protein. The purpose of the present study was to examine the hypothesis that the two carboxyl groups of cosalane could be sacrificed through conjugation to amino acids, and the anti-HIV activity still be retained, provided that at least two new carboxyl groups are contributed by the amino acid residues.

Synthesis and Chemistry of Fullerene Derivatives Bearing Phosphorus Substituents. Unusual Reaction of Phosphines with Electron-Deficient Acetylenes and C(60).

A unique method to introduce phosphorus substituents onto C(60) is based on the reaction of phosphines with acetylenes and C(60). Treatment of C(60) with phosphines (PR(3)) and electron-deficient acetylenes (A) in toluene at ambient temperature gave fullerene derivatives (1, R = C(6)H(5) and A = MeO(2)CC&tbd1;CCO(2)Me; 2, R = C(6)D(5) and A = MeO(2)CC&tbd1;CCO(2)Me; 3, R = C(6)H(5) and A = EtO(2)CC&tbd1;CCO(2)Et; 4, R = p-CH(3)C(6)H(5) and A = MeO(2)CC&tbd1;CCO(2)Me; 6, R = C(6)H(5) and A = trans-MeO(2)CC&tbd1;CCH=CHCO(2)Me) consisting of a phosphorus ylide group and a cyclopropane ring on the fullerene moiety in good to excellent yields. The structures of these ylide derivatives are determined on the basis of their spectral data and single-crystal X-ray diffraction measurements. All these ylides show temperature-dependent NMR spectra that can be rationalized on the basis of interchange between two Z,E isomers and restricted rotation of the substituents on the fullerene moiety. Based on the known chemistry of phosphines and acetylenes, we propose a mechanism to account for the formation of these ylide derivatives. Phosphine ylides 1 and 4 readily undergo protonation and decarboxylation in the presence of acid to give phosphonium salts 7 and 8, respectively.

Fullerene Derivatives Bearing a Phosphite Ylide, Phosphonate, Phosphine Oxide, and Phosphonic Acid: Synthesis and Reactivities.

Treatment of phosphites (P(OR)(3)) and MeO(2)CCCCO(2)Me with C(60) affords the corresponding fullerene derivatives (1, R = Me; 2, R = Et; 3, R = n-Bu) consisting of a phosphite ylide group and a cyclopropane ring on the fullerene moiety in high yields. NMR data indicate that all phosphite ylides 1-3 exist as mixtures of E and Z isomers. Under similar reaction conditions, the reaction of phosphinite PPh(2)(OMe) and MeO(2)CCCCO(2)Me with C(60) gives ylide 4. Ylides 1-3 readily undergo hydrolysis with HBr to give corresponding phosphonates 5-7 in excellent yields, while ylide 4 reacts with hydrobromic acid to afford phosphine oxide 8. A mechanism is proposed to account for the formation of these phosphonate derivatives. Further treatment of phosphonate derivative 5 with trimethylsilyl iodide followed by water gave phosphonic acid derivative 9 in 83% yield.

alpha-Carbonyl Radical Cyclization Approach toward Angular Triquinanes: Total Synthesis of Enantiomerically Pure (-)-5-Oxosilphiperfol-6-ene.

An alpha-carbonyl radical cyclization approach toward synthesis of angular triquinanes is described. As a model study, conjugate addition of 4-(trimethylsilyl)-3-butynylmagnesium chloride to enone 7 followed by trapping of the enolate with chlorotrimethylsilane gave trimethysilyl enol ether 8. Iodination of 8 with a mixture of NaI and m-CPBA afforded iodo ketone 6. Radical cyclization of 6 effected by Bu(3)SnH and AIBN gave 5. Epoxidation of 5 with m-CPBA yielded epoxy ketone 9. Desilylation and rearrangement of 9 by formic acid gave aldehyde 4. Aldol condensation and dehydration furnished angular triquinane skeleton 3. Total synthesis of (-)-5-oxosilphiperfol-6-ene (1) was accomplished in 12 steps starting from keto ester 14 based on this route. Conjugate addition of 3-hexynylmagnesium bromide to chiral ester 13 followed by treatment with chlorotrimethylsilane gave intermediate 15. Iodination of 15 with a mixture of NaI and m-CPBA gave alpha-iodo ester 12. Intramolecular radical cyclization of 12 gave ester 11. Reduction of 11 by LiAlH(4) yielded alcohol 16. On treatment with m-CPBA, alcohol 16 was converted to the corresponding epoxide 17, which was subjected to the epoxy-ketone rearrangement using BF(3) etherate as a catalyst to give ethyl ketone 18. Subsequent oxidation of 18 with PCC afforded aldehyde 10. Intramolecular aldol condensation of 10 yielded tricyclic compound 19. Methylation of 19 gave 20. Conjugate addition of lithium dimethylcuprate to 20 followed by trapping of the resulting enolate with chlorotrimethylsilane gave 21. Oxidation of 21 by DDQ afforded enantiomerically pure (-)-5-oxosilphiperfol-6-ene (1). Racemic (+/-)-1was also synthesized in the same manner in order to determine the optical purity of chiral product (-)-1. The gas chromatographic analysis with a chiral column proved that 1 has high enantiomeric purity. A single-crystal X-ray analysis of 2,4-dinitrophenylhydrazone 22 was performed to unambiguously confirm the stereochemistry of 19.