Radical-mediated thiodesulfonylation of the vinyl sulfones: Access to (α-fluoro)vinyl sulfides.

Radical-mediated thiodesulfonylation of the vinyl and (α-fluoro)vinyl sulfones, derived from aldehydes and ketones, with aryl thiols in organic or aqueous medium provided access to vinyl and (α-fluoro)vinyl sulfides. The vinyl sulfides were formed predominantly with E stereochemistry independent of the stereochemistry of the starting vinyl sulfones.

Synthesis of 5'-functionalized nucleosides: S-Adenosylhomocysteine analogues with the carbon-5' and sulfur atoms replaced by a vinyl or halovinyl unit.

Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5' were prepared employing cross-metathesis, Negishi couplings, and Wittig reactions. Metathesis of the protected 5'-deoxy-5'-methyleneadenosine or uridine analogues with six-carbon amino acids (homoallylglycines) in the presence of Grubbs catalysts gave nucleoside analogues with the C5'-C6' double bond. Alternatively, the Pd-catalyzed cross-coupling between the protected 5'-deoxy-5'-(iodomethylene) nucleosides and suitable alkylzinc bromides also provided analogues with alkenyl unit. Stereoselective Pd-catalyzed monoalkylation of 5'-(bromofluoromethylene)-5'-deoxyadenosine with alkylzinc bromides afforded adenosylhomocysteine analogues with a 6'-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-l-homocysteine hydrolases.

Development of a distance education program by a Land-Grant University augments the 2-year to 4-year STEM pipeline and increases diversity in STEM.

Although initial interest in science, technology, engineering and mathematics (STEM) is high, recruitment and retention remains a challenge, and some populations are disproportionately underrepresented in STEM fields. To address these challenges, the Microbiology and Cell Science Department in the College of Agricultural and Life Sciences at the University of Florida has developed an innovative 2+2 degree program. Typical 2+2 programs begin with a student earning an associate's degree at a local community college and then transferring to a 4-year institution to complete a bachelor's degree. However, many universities in the United States, particularly land-grant universities, are located in rural regions that are distantly located from their respective states' highly populated urban centers. This geographical and cultural distance could be an impediment to recruiting otherwise highly qualified and diverse students. Here, a new model of a 2+2 program is described that uses distance education as the vehicle to bring a research-intensive university's life sciences curriculum to students rather than the oft-tried model of a university attempting to recruit underrepresented minority students to its location. In this paradigm, community college graduates transfer into the Microbiology and Cell Science program as distance education students to complete their Bachelor of Science degree. The distance education students' experiences are similar to the on-campus students' experiences in that both groups of students take the same department courses taught by the same instructors, take required laboratory courses in a face-to-face format, take only proctored exams, and have the same availability to instructors. Data suggests that a hybrid online transfer program may be a viable approach to increasing STEM participation (as defined by enrollment) and diversity. This approach is particularly compelling as the distance education cohort has comparable grade point averages and retention rates compared to the corresponding on-campus transfer cohort.

Stereoselective synthesis of sugar-modified enyne analogues of adenosine and uridine. Interaction with S-adenosyl-L-homocysteine hydrolase and antiviral and cytotoxic effects.

Sonogashira coupling of (E)-6'-iodohomovinyl nucleosides 1 with (trimethylsilyl)acetylene gave the conjugated 8'-(trimethylsilyl)enyne derivatives of the adenosine 2a and uridine 2b with expected E-stereochemistry. Desilylation of 2a,b with tetrabutylammonium fluoride followed by treatment with N-iodosuccinimide/AgNO(3) afforded 8'-iodoenynes 4a,b. Analogous coupling of (Z)-6'-iodohomovinyl nucleosides 7a,b produced (Z)-8'-(trimethylsilyl)enynes 8a,b, which were deprotected with aqueous trifluoroacetic acid to give the Z-enynes 9a,b. Stereoselective coupling of the adenosine 4'-acetylenic 11 and ethyl (Z)-3-bromoacrylate followed by deprotection gave the conjugated enyne system attached in the reverse orientation at C4' 13. Because of their diverse stereochemical attributes, deprotected enyne analogues 5a, 6a, 9a, and 13 derived from adenosine require a different vicinity for binding with S-adenosyl-l-homocysteine (AdoHcy) hydrolase and/or addition of enzyme-bound water across the conjugated enyne system. Enyne 5a and 8'-iodoenyne 6a produced time-dependent and concentration-dependent inhibition of AdoHcy hydrolase (K(i), 0.55 and 118.5 microM, respectively). No reduction in NAD(+) content of the enzyme and no iodide ion released were observed upon incubation of 6a with the enzyme, while incubation of 5a produced 30% reduction in the NAD(+) content of the enzyme. No specific antiviral activity was noted for 5a,b, 6a,b, 9a,b, and 13 against any of the viruses tested; the E-iodoenynes 6a and 6b inhibited HIV-1 virus (IC(50), 1.1 and 1.8 microM; selectivity index, 7 and 3, respectively). The E-enyne 5a showed activity against cytomegalovirus at a concentration (EC(50), 30 microM) that was 3- to 10-fold lower than the cytotoxic concentration.

Sugar-modified conjugated diene analogues of adenosine and uridine: synthesis, interaction with S-adenosyl-L-homocysteine hydrolase, and antiviral and cytostatic effects.

Moffatt oxidation of 2',3'-O-isopropylideneuridine (1a) and treatment of the crude 5'-aldehyde with formylmethylene-stabilized Wittig reagent gave the vinylogously extended 7'-aldehyde2a. Condensation of 2a with ethoxycarbonyl- or dibromomethylene phosphorane reagents gave the conjugated dienes 6a and 4a, respectively. Deacetonization gave diene ester 7a [5'(E),7'(E); with s-trans conformation] and dibromodiene 5a [5'(E)], respectively. Analogously, 2',3'-O-isopropylideneadenosine (1b) was Wittig-extended into the conjugated dibromodiene 5b [5'(E)] and dienoic ester 7b [5'(E),7'(E)]. Furthermore, palladium-catalyzed coupling of the vinyl 6'(E)-stannanes 14 with (E) and (Z) ethyl 3-iodoacrylate gave stereodefined access to dienoic esters 7 (E,E) and 16 (E,Z). Incubation of AdoHcy hydrolase with 100 microM of 5b resulted in partial inhibition of the enzyme without any apparent change in the enzyme's nicotinamide adenine dinucleoside (NAD(+)) content. In contrast, 7b and 16b produced time- and concentration-dependent inactivation of S-adenosyl-L-homocysteine (AdoHcy) hydrolase producing significant decreases in the enzyme's NAD(+) content. However, 7b and 16b upon incubation with AdoHcy hydrolase were not metabolized suggesting that these compounds are type I mechanism-based inhibitors. No specific antiviral activity was noted for 5a,b, 7a,b, and 16a,b against any of the viruses tested; dibromodiene 5b proved cytotoxic at a concentration > or =6.7 microM and cytostatic at > or =11 microM, while dienoic esters 16a,b showed activity against both varicella-zoster virus (at 10 microM, 16a) and cytomegalovirus (at 10 microM, 16a; 18 microM, 16b).

Stereocontrolled synthesis of diene and enyne sugar-modified nucleosides and their interaction with S-adenosyl-L-homocysteine hydrolase.

Conjugated diene 5-7 and enyne 8 analogs derived from adenosine and uridine were synthesized employing Pd-catalyzed cross-coupling reactions.

Application of germyldesulfonylation reactions to the synthesis of germanium-containing nucleoside analogues.

Treatment of the protected (E)-5'-deoxy-5'-[(p-toluenesulfonyl)methylene]uridine and adenosine derivatives with tributyl- or triphenylgermane hydride (AIBN/toluene/Delta) effected radical-mediated germyldesulfonylations to give 5'-(tributyl- or triphenylgermyl)methylene-5'-deoxyuridine and adenosine derivatives as single (E)-isomers. Analogous treatment of 2'-deoxy-2'-[(phenylsulfonyl)methylene]uridine with Ph(3)GeH afforded the corresponding vinyl triphenylgermane product. Stereoselective halodegermylation of the (E)-5'-(tributylgermyl)methylene-5'-deoxy nucleosides with N-iodosuccinimide or N-bromosuccinimide provided the Wittig-type (E)-5'-deoxy-5'-(halomethylene) nucleosides quantitatively, while no halodegermylations was observed with the 5'-deoxy-5'-(triphenylgermyl)methylene counterparts. Treatment of the vinyl trialkylgermanes with aqueous trifluoroacetic acid effected protiodegermylation, while vinyl triarylgermanes were stable under the acidic conditions.