J. Walter Sowell

Synthesis and antiviral/antitumor evaluation of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes and related compounds as a new class of diarylsulfones.

Based on general SARs previously described for anti-HIV-1 diarylsulfone derivatives, a series of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes has been prepared and evaluated as potential antiviral and antitumor agents. In cell culture, some of the 2-aminothiophenes exhibited moderate and selective activity against HIV-1, with 2-amino-3-(2-nitrophenylsulfonyl)thiophene (7e) being most attractive (EC(50)=3.8 microg/mL, CC(50)=>100 microg/mL). In broad-spectrum antiviral assays, the 3-arylsulfonyl-2-(trifluoroacetamido)thiophenes (8c-g) and 2-acetamido-3-arylsulfonyl-5-nitrothiophenes (9f-g) proved considerably active (IC(50)=0.1-10 microg/mL) against human cytomegalovirus (CMV) and/or varicella zoster virus (VZV). Based on the activity of the trifluoroacetamides, ring-modified furan, N-(substituted)pyrrole, phenyl, and 3,4-thiophene analogues were prepared, and these compounds were also active against CMV and/or VZV, with the notable exception of the 3,4-thiophene derivative. In contrast to other amines, the 2-aminopyrrole precursors (13a-d) also exhibited potent activity against CMV. Unfortunately, most of these compounds displayed significant cytotoxicity against human fibroblasts, the cells supporting CMV and VZV replication, and thus selectivity indices were low. The most notable exception to this was the naphthyl-substituted aminopyrrole 13d, which exhibited both potent (IC(50)=0.3 microg/mL) and selective (CC(50)=>50 microg/mL) activity against CMV. Finally, thiophene aryl amides 8i-k displayed moderate in vitro activity against certain leukemia, breast, and colon cancer cell lines.

Synthesis and investigation of urea compounds as transdermal penetration enhancers

Abstract Twelve urea and thiourea compounds were examined for their transdermal penetration enhancing properties in vitro using hairless mouse skin and hydrocortisone as a model drug. Skins were pretreated for 1 h with the enhancer in propylene glycol before application of the drug also in propylene glycol. Enhancement ratios ( ER ) were calculated for permeability coefficient ( P ), 24 h receptor concentration ( Q 24 ), and skin content of drug ( SC ) and compared to control values (no enhancer present). Control values for permeability coefficients were 0.71±0.27 cm h −1 , 24 h receptor concentration: 11.9±3.4 μ M, and skin content of drug 44.6±18.5 μ g g −1 . The most effective enhancer of the series was 1-dodecyl-3-methylthiourea. This enhancer produced the highest values for all three penetration parameters with a permeability coefficient 4.7±1.8×10 −4 cm h −1 ( ER P 6.6), a 24 h receptor concentration of 62.7±16.3 μ M ( ER Q 24 5.3), and a skin content of 90.1±17.7 μ g g −1 ( ER SC 2.0). A structure-activity relationship was observed in that the thio-substituted analogs were more effective enhancers than the oxygen-containing compounds. Although these compounds show promise as penetration enhancers, further study is needed to determine their effectiveness with other drugs and their irritation potential.

Synthesis of 7α-substituted derivatives of 17β-estradiol

Abstract Estrogen receptor (ER) pure antagonists such as ICI-182,780 (fulvestrant) are effective alternatives to tamoxifen (an ER antagonist/weak partial agonist) in the treatment of postmenopausal, receptor-positive human breast cancers. Structurally, these pure antagonists contain the basic core structure of 17β-estradiol (E 2 ) with a long side chain attached to its C-7α position. We explored and compared in this study various synthetic routes for preparing a number of C-7α-substituted derivatives of E 2 , which are highly useful for the design and synthesis of high-affinity ER antagonists, ER-based imaging ligands, and other ER-based multi-functional agents. Using E 2 as the starting material and 1-iodo-6-benzyloxyhexane as a precursor for the C-7α side chain, a seven-step synthetic procedure afforded 3,17β-bis(acetoxy)-7α-(6-hydroxyhexanyl)-estra-1,3,5(10)-triene (one of the derivatives prepared) in an overall yield of ∼45% as compared to other known procedures that afforded substantially lower overall yield (8–27%). The synthetic steps for this representative compound include: (1) protection of the C-3 and C-17β hydroxyls of E 2 using methoxymethyl groups; (2) hydroxylation of the C-6 position of the bismethoxymethyl ether of E 2 ; (3) Swern oxidation of the C-6 hydroxy to the ketone group; (4) C-7α alkylation of the C-6 ketone derivative of E 2 ; (5) deprotection of the two methoxymethyl groups; (6) reprotection of the C-3 and C-6 free hydroxyls with acetyl groups; (7) removal of the C-6 ketone and the benzyl group on the side chain by catalytic hydrogenation in acetic acid. As predicted, two of the representative C-7α-substituted derivatives of E 2 synthesized in the present study retained strong binding affinities (close to those of E 2 and ICI-182,780) for the human ERα and ERβ subtypes as determined using the radioligand–receptor binding assays.

Synthesis of Substituted 2-Aminopyrrole Analogs of Lidocaine I

The synthesis, local anesthetic, and antiarrhythmic properties of nine 2-diethylaminoacetamido-3-cyano-4-methyl-5-substituted pyrroles are described. All compounds showed local anesthetic activity by the guinea pig wheal test and antiarrhythmic activity for chloroform-induced ventricular arrhythmias in mice.

1,3-Oxazino[4,5-b]indole-2,4-(1H,9H)-diones and 5,6-dimethylpyrrolo-[2,3-d]-1,3-oxazin-2,4-(1H,7H)-diones as serine protease inhibitors

Abstract 9-Substituted-1,3-oxazino[4,5-b]indole-2,4-(1 H ,9 H )-diones and 7-substituted-5,6-dimethylpyrrolo[2,3-d]-1,3-oxazin-2,4-(1 H ,7 H )-diones are synthesized from indolo- or pyrrolo-β-enamino t -butyl esters in moderate yield. Certain compounds are found to inhibit human leukocyte elastase (HLE) and chymotrypsin selectively.

Chemical synthesis of two novel diaryl ether dimers of estradiol-17β

We recently detected the formation of estradiol-17beta (estradiol) dimers, linked together through a diaryl ether bond between the C-3 phenolic oxygen of one estradiol molecule and the 2- or 4-position aromatic carbon of another estradiol, following incubations of [3H]estradiol with human liver microsomes or cytochrome p450 enzymes in the presence of NADPH. Using estradiol as the starting material, we designed a four-step method for the chemical synthesis of these two estrogen dimers with the Ullmann condensation reaction as a key step. Step 1: Synthesis of 2- or 4-bromoestradiol from estradiol. Step 2: Protection of the C-3 phenolic hydroxyl group of the 2- or 4-bromoestradiol. Step 3: The Ullmann condensation reaction between the phenol-protected bromoestradiol and the estradiol potassium salt under our modified reaction conditions (with a 41% product yield). Step 4: Removal of the C-3 benzyl group by catalytic hydrogenation. The chromatographic and various spectrometric properties of the two synthesized compounds were identical to those metabolically formed by human cytochrome p450 3A4.