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The lack of effective methods to perform direct β-selective glycosylation reactions with 2-deoxy-1,4-dithio-D-erythro-pentofuranosides has long been a significant stumbling block for the multi-gram synthesis of 4'-thio-2'-deoxy nucleosides. In addition, previously reported methods for the preparation of appropriately substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides have proven problematic for large scale synthesis. To address these issues, herein we describe the modification and optimization of previously reported methods to allow for the convenient large scale synthesis of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides. Furthermore, we describe the development of reaction conditions for β-selective glycosylation reactions of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides with both N4-benzoylcytosine and 5-aza-cytosine to enable the practical multi-gram syntheses of the clinical candidates 4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd). Taken together, these new synthetic developments have made possible the preclinical and early clinical development of these important anticancer agents at the National Cancer Institute.

The lack of effective methods to perform direct β-selective glycosylation reactions with 2-deoxy-1,4-dithio-D

The development of high-load, soluble oligomeric sulfonate esters, generated via ROM polymerization, and their utility in the facile benzylation of an array of amines is reported. These polymeric sulfonate esters exist as free-flowing powders, are stable at refrigerated temperatures, and are readily dissolved in CH(2)Cl(2). Following the benzylation event, purification is attained via simple filtration, followed by solvent removal to deliver the desired benzylated product in good to excellent yield and high purity. [structure: see text]

Oxidation of alpha-conidendrin (3) by Fremy's salt favored formation of an o-quinone (4) at the pendant aromatic ring as opposed to the fused aromatic ring. Quinone reduction and phenolic methylation, followed by lactone reduction, and subsequent oxidation by dichlorodicyanoquinone produced sikkimotoxin oxabicyclooctane (7), while oxidation with cupric sulfate/potassium persulfate gave sikkimotoxin dioxatricyclodecane (8).

The parallel synthesis of gamma-turn-inspired peptidomimetic libraries has been demonstrated through two approaches toward the preparation of 1,4-diazepin-5-ones. In the first approach, 1,4-diazepin-5-ones scaffolds were prepared on gram scale and subsequently diversified to produce libraries. In a second approach, libraries of 1,4-diazepin-5-ones were produced directly through a three-component strategy that maximizes the diversity obtained in a single step.

Efforts to synthesize potential methionine aminopeptidase inhibitors is described. Preliminary SAR and docking studies served as a guide to design the compound libraries. “Chromatography-free” synthesis of various heterocyclic amides was realized by using a high-load, soluble coupling reagent derived via ring-opening metathesis polymerization (ROMP). Subsequent microwave-assisted Suzuki reactions with ortho-substituted arylboronic acids, followed by chromatographic purification afforded a 55-member library in high yields and purities. While the biological testing was not satisfactory, concurrent X-ray crystallography studies revealed key structural features essential for inhibition of methionine aminopeptidase, which directed fruitful results reported in the accompanying manuscript. In addition, in silico Lipinksi profiles and ADME properties of the library are also reported.

The development of high-load, oligomeric benzylsulfonium salts, generated via ring-opening metathesis polymerization, and their utility in facile benzylations of various nucleophiles is reported. These oligomeric sulfonium salts exist as free-flowing powders and are stable at room temperature. After the benzylation event, purification is attained via simple dry load/filtration, followed by solvent removal to deliver products in excellent yield and purity.

Dioxatricyclodecane, oxabicyclooctane, and benzodihydropyran derivatives of alpha-conidendrin (ACON), podophyllotoxin (PT), and sikkimotoxin (SK) were prepared to learn which methyleneoxy bridging modes and arene and aryl substituents coincided with high cytotoxicity. PT-derived dioxatricyclodecane 14 showed in vitro activity at 10(-8) M. SK analogue 12 was less active, and ACON analogue 11 was inactive at 10(-4) M. In vivo intraperitoneal and subcutaneous activities of 14 were observed. In vitro cytotoxicities were higher for oxabicyclooctanes when hydroxymethyl group and methyleneoxy bridge were cis, as in deoxypicropodophyllin analog20, rather than trans, as in PT analogue 5. Acetylation of the hydroxymethyl group of 20 lowered activities, whereas acetylation of 5 increased or lowered activities. Reduction of the hydroxymethyl group of 5 to a methyl group increased cytotoxicities. Molecular dynamics indicated the THN scaffold of benzodihydropyrans was conformationally mobile, but scaffolds of oxabicyclooctanes and dioxatricyclodecanes were immobile. Each of three PT-benzodihydropyrans was less active than its oxabicyclooctane counterpart.

Derivatives of alpha-conidendrin, podophyllotoxin, and sikkimotoxin were prepared to evaluate the cytotoxic contributions of C-4 configuration and pendant and fused arene substitutions. Dimethyl-alpha-conidendryl alcohol (5), 9-deoxypodophyllol (6), and 9-deoxysikkimol (17) were dehydrated to their respective oxolane derivatives 4, 3, and 9. Diols 5 and 6 were converted via oxabicyclo[3.2.1]octanols 10 and 14 to target oxolanes 8 and 7 where C-4 had been inverted relative to that in 3 and 4. Cytotoxicities of the five oxolanes were determined in two drug-sensitive human leukemia and two multidrug-resistant cell lines expressing P-glycoprotein or multidrug-resistance associated protein (MRP). Changing the pendant arene configuration or replacing a m-methoxy by hydrogen resulted in a 100-fold cytotoxicity loss. Replacing a methylenedioxy group in the fused arene by two methoxy substituents reduced cytotoxicity by 10-fold. Drug-resistant cell lines were equally resistant to compounds 3, 4, 8, and 9 indicating that these four compounds do not serve as substrates of the transport proteins P-glycoprotein and MRP.