Inhibition of tubulin polymerization by select alkenyldiarylmethanes.

During studies on the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), analogues were discovered that exhibit low micromolar and submicromolar cytotoxicities. Since the ADAMs are structurally related to the tubulin polymerization inhibitor CC-5079, a set of 14 ADAMs were tested for inhibition of tubulin polymerization in an attempt to identify the biological target responsible for their cytotoxicity. The results indicate that, overall, the ADAMs are poor inhibitors of tubulin polymerization. However, the two most cytotoxic compounds, 15 and 16, are in fact active as inhibitors of tubulin assembly with IC(50) values of 3.7+/-0.3 and 2.8+/-0.2 microM, respectively, and they both inhibit the binding of colchicine to tubulin. Both compounds were investigated for anticancer activity in the National Cancer Institute's panel of 60 human cancer cell lines, and both compounds consistently displayed submicromolar cytotoxicities with mean-graph midpoint (MGM) values of 0.31+/-0.08 and 0.47+/-0.09 microM, respectively.

Synthesis, drug release and anti-HIV activity of a series of PEGylated zidovudine conjugates.

A series of methoxy poly(ethylene glycol)-succinyl-5'-O-zidovudine conjugates (mPEG-succinyl-AZT) with different molecular weight (M(w): 750 Da, 2, 5 or 10 kDa) of mPEG were synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy, and matrix-assisted laser desorption/ionization time of flight mass (MALDI TOF MS) spectrometry analysis. All conjugates showed good stability in vitro release experiments, and good anti-HIV activity and low cytotoxicity in MT-4 cells, in which, mPEG(750)-succinyl-AZT exhibited good inhibition to wild-type viruses (strains IIIB and ROD) with EC(50) values of 0.11 and 0.090 µmol/L, respectively, and it showed no cytotoxicity up to 110 µmol/L. Oral pharmacokinetic study in rats showed the half-life time (T(1/2)) of all conjugates are prolonged compared to free AZT. Especially, mPEG(750)-succinyl-AZT displayed a ~2.3-fold prolonged half-life and approximately 224% increased bioavailability of AZT.

Synthesis, in vitro and in vivo release kinetics, and anti-HIV activity of a sustained-release prodrug (mPEG-AZT) of 3'-azido-3'-deoxythymidine (AZT, Zidovudine).

A poly(ethylene glycol) (PEG) conjugate of 3'-azido-3'- deoxythymidine (AZT, zidovudine) was designed and synthesized as a novel sustained-release prodrug. In the synthetic process, a succinate diester spacer was used to covalently couple AZT with methoxy poly(ethylene glycol) (mPEG; MW=2000). The conjugate was characterized by Fourier transform infrared (FTIR) and NMR spectroscopies and matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MS). The in vitro release was determined in hydrochloride (HCl) solution (pH 1.2) and phosphate-buffered solution (PBS; pH 6.8), which showed the release rate of AZT from the conjugate was slower than that from the free drug, suggesting its possible increased retention in gastrointestinal conditions. Pharmacokinetic properties were evaluated experimentally by oral administration in mice. Compared to free AZT, the absorption half-life (t1/2ka) and elimination half life (t1/2ß) of AZT released from the conjugate were both extended to 0.51±0.03 h (p <0.01) and 2.94±0.24 h (p <0.01), respectively. Evaluation of the in vitro anti-HIV activities showed mPEG-AZT exhibited good inhibition of HIV-1, with an EC(50) value of 0.0634 µM, but it is lower than that of free AZT. These results show that the conjugate is capable of releasing the parent drug in a sustained profile, potentially providing a feasible alternative to oral administration of AZT in a clinical setting.

Synthesis and in vitro evaluation of S-acyl-3-thiopropyl prodrugs of Foscarnet.

A new enzyme-labile group called S-acyl-3-thiopropyl group (SATP) has been synthesized from allylic esters of phosphonate. After demonstration of the enzyme-labile character of the SATP in cellular extracts, it has been introduced onto the phosphonate moiety of PFA (Foscarnet) to obtain potential lipophilic prodrugs. To ponder the lipophilicity of the triesters of PFA, esters of monomethylether of polyethyleneglycols and of thioglycerol were introduced on the PFA carboxylate moiety. The SATP groups were introduced in an attempt to deliver PFA after bioactivation inside the cells. The PFA prodrugs were evaluated in vitro for their activity against human immunodeficiency viruses (HIV-1 and HIV-2).