The Synthesis of Novel 6,5- and 6,6-Membered Fused Heterocyclic Compounds Derived from Thymine

Abstract

Novel pyrimido[1,2-a]pyrimidinones 14, 15 and 16 and imidazo[1,2-a] pyrimidinones 19 and 20, designed as conformationally constrained analogues of 1-(3-amino-2-hydroxypropyl)thymine and 1-(2-amino-3-hydroxypropyl)thymine, respectively, were synthesized by the ring-opening/ ring-closure rearrangement of the corresponding byciclic oxygen-containing amino compounds 12 and 17.     

Design and synthesis of 6,6-fused heterocyclic amides as raf kinase inhibitors

Compounds belonging to several scaffolds-quinazolines, quinolines and quinoxalines-were designed and synthesized as Raf kinase inhibitors. Scaffolds were assessed for in vitro Braf(V600E) inhibition, and overall kinase selectivity. Pharmacokinetic parameters for one of the scaffolds were also determined.     

Synthesis of novel 4'-substituted 16-membered ring macrolide antibiotics derived from leucomycins

A series of novel 4'-substituted 16-membered ring macrolides was synthesized by the cleavage of the mycarose sugar and subsequent modification of 4'-hydroxyl group. This new class of macrolides antibiotics is acid stable. The synthetic methodology described here is expected to find application in the synthesis of new generation of macrolides that target the emerging bacterial resistance.     

Synthesis of 10- and 9-membered dilactams derived from aspartic and glutamic acids.

9- and 10-membered bridged dipeptides derived from L-aspartic acid and L- or D-glutamic acid were synthesized using aminoacyl incorporation reaction. Key intermediates containing internal pyroglutamyl moiety were prepared via side chain to backbone cyclization of related protected dipeptide derivatives of glutamic acid.     

Syntheses of fused heterocyclic compounds and their inhibitory activities for squalene synthase.

A variety of fused heterocyclic compounds (2-11) were synthesized as a modification of the lead compound 1a and evaluated for their inhibition of squalene synthase. 4,1-Benzothiazepine derivative 2, 1,4-benzodiazepine derivative 6, 1,3-benzodiazepine derivative 7, 1-benzazepine derivative 9, and 4,1-benzoxazocine derivative 10 potently inhibited squalene synthase activity, whereas the 4,1-benzoxazepine derivatives 1 was the most potent inhibitor. 4,1-Benzothiazepine S-oxide derivative 4, 1,4-benzodiazepine derivative 5, 1,3,4-benzotriazepine derivative 8, and 1,2,3,4-tetrahydroquinoline derivative 11 were found to be weakly active. Comparison of the X-ray structures of these compounds (1a, 2, 4, 5, 7 and 10) suggests that orientation of the 5- (or 6)-phenyl group is important for activity.     

Design and synthesis of novel chemokine analogs derived from vMIP-II

Stepwise solid phase synthesis using the Fmoc chemistry is reported for a panel of 71-residue and novel unnatural chemokine analogs derived from vMIP-II. This demonstrates the feasibility of using this synthetic method to generate de novo designed protein ligand molecules to study the biology and pharmacology of chemokine receptors.     

The further investigation of physical and photochemical properties of quasimetacyclophane derived from thymine

The thymine derived quasimetacyclophane exist in two conformers $\text{a}$ and $\text{b}$. The absorption spectra of $\text{a}$ and $\text{b}$ were evaluated and the conformational equilibrium in different solvents /H₂O : EtOH/ were examined. The rate constant k_?1 for reaction $\text{b}\text{→}\text{a}$ was established as well as E_a.     

Design and synthesis of novel D-ring fused steroidal heterocycles

Using dehydroepiandrosterone as the starting material, we have synthesized a series of steroid analogs possessing a D-ring fused with heterocycles which are pyridine, imidazo [2,1-b]thiazoles or substituted thiazole imines. All the final structures are first reported and identified by NMR and MS spectroscopys, the yields of these products are moderate to good and the reaction conditions are mild. The cytotoxicity of the synthesized compounds against EC-109(human esophageal carcinoma), EC-9706(human esophageal carcinoma), MGC-803(human gastric carcinoma) were investigated.     

Design and diversity-oriented synthesis of novel 1,4-thiazepan-3-ones fused with bioactive heterocyclic skeletons and evaluation of their antioxidant and cytotoxic activities

This study has achieved the design and diversity-oriented synthesis of novel 1,4-thiazepine derivatives embedded with carbazole, pyrazole or isoxazole motif via microwave-assisted multicomponent reactions under solvent-free condition, thus providing a green and facile access to 1,4-thiazepine derivatives with prominent features of high structural diversity, short reaction time, high yields and environmental friendliness. More importantly, these novel compounds have been subjected to the test of in vitro antioxidant and cytotoxic activities, resulting in the finding that these 1,4-thiazepine derivatives not only have significant antioxidant activity, but also exhibit remarkably selective cytotoxicity to carcinoma cell line HCT 116.     

The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics

A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.     

The synthesis and evaluation of 10- and 12-membered ring benzofused enediyne amino acids

The enediyne moiety is a versatile functional group found in natural anticancer and anti-infective agents, undergoing the Bergman cyclization reaction to afford a diradical which cleaves double-stranded DNA. We have incorporated the enediyne group into 10- (4-10) and 12-membered ring (11) cyclic amino acids and dipeptides, respectively, and explored their relative reactivity toward cyclization, varying N-substitution in the case of the 10-membered ring substrate, which gave the expected cyclization products in good yields when using either thermal conditions in the presence or absence of microwave irradiation. The N-tosyl substituted derivative (4) was shown to nick double-stranded supercoiled DNA. N-Arylsulfonyl substitution on the ring promoted the cyclization, when compared to N-mesyl or acyl substitution, possibly because of a pi-pi stacking effect as an endo-relationship of the aryl group with the enediyne was demonstrated in both the solid state and in solution. The 12-membered ring enediyne dipeptide (11) was inert to the Bergman cyclization under a variety of conditions. When this substrate was irradiated with ultraviolet light, regio- and stereospecific reduction was observed in which one of the alkynes was reduced to a Z-olefin (47).     

Stereoselective synthesis and anti-inflammatory activities of 6- and 7-membered dioxacycloalkanes

A class of 5-trifluoroacetylamino-1,3-dioxacycloalkanes, 5-benzoylamino-1,3-dioxacycloalkanes, and 5-amino-1,3-dioxacycloalkane compounds were stereoselectively synthesized as potential anti-inflammatory drug candidates. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model, from which multiple compounds possessing anti-inflammatory properties which surpass aspirin were identified; these compounds were then compared to establish structure-activity relationships.     

The synthesis and in vitro testing of structurally novel antibiotics derived from acylnitroso Diels-Alder adducts

The structural similarity between beta-lactam antibiotics, such as penicillin, and isoxazolidine-3,5-dicarboxylic acids led to the hypothesis that isoxazolidine-3,5-dicarboxylic acids could be effective analogs of beta-lactam antibiotics. The syntheses of relevant isoxazolidine-3,5-dicarboxylic acids from acylnitroso Diels-Alder adducts and subsequent biological testing have shown that these first examples are inhibitors of Escherichia coli X580.     

Cytotoxic heterocyclic triterpenoids derived from betulin and betulinic acid

The aim of this work was to synthesize a set of heterocyclic derivatives of lupane, lup-20(29)-ene, and 18α-oleanane, and to investigate their cytotoxic activities. Some of those heterocycles were previously known in the oleanane (allobetulin) group; however, to our knowledge the syntheses and biological activities of lupane heterocycles have not been reported before. Starting from betulin (1) and betulinic acid (2), we prepared 3-oxo compounds and 2-bromo-3-oxo compounds 3-10, 2-hydroxymethylene-3-oxo compounds 11-13 and β-oxo esters 14-16. Condensation of these intermediates with hydrazine, phenylhydrazine, hydroxylamine, or thiourea yielded the pyrazole and phenylpyrazole derivatives 17-22, pyrazolones 23-25, isoxazoles 26 and 27, and thiazoles 28-31. Fifteen compounds (14-16, 18-25, and 29-32) have not been reported before. The cytotoxicity was measured using panel of seven cancer cell lines with/without MDR phenotype and non tumor MRC-5 and BJ fibroblasts. The preferential cytotoxicity to cancer cell lines, particularly to hematological tumors was observed, the bromo acids 5, 6 showed highest activity and selectivity against tumor cells.     

Microwave promoted one-pot synthesis of novel A-ring fused steroidal dehydropiperazines

The preparation of ring-A fused steroidal dehydropiperazine at the 3,4-position is herein described. The novel steroidal dehydropiperazines were prepared from the annulation reaction of ethylenediamine with 3-keto-4-en steroids in a one-pot reaction under microwave irradiation. The key step involves base catalysed aerial oxidation of the C-6 methylene group followed by cyclocondensation of ethylenediamine via Michael addition reaction.     

Synthesis of 9-membered dilactams derived from 1,3-diaminopropionic and glutamic acids.

Previously unknown 9-membered bridged dipeptides derived from l or d isomers of 1,3-diaminopropionic acids and l-glutamic acid were synthesized using aminoacyl incorporation reaction. Key intermediates containing internal pyroglutamyl moiety were prepared via side chain to backbone cyclization of related protected dipeptide derivatives of glutamic acid.