Anomer-selective inhibition of glycosidases using aminocyclopentanols

[reaction: see text] (1S,2S,3S,4R,5R)-4-amino-5-(hydroxymethyl)cyclopentane-1,2,3-triol 1 is prepared stereoselectively from D-lyxose and displays anomer-selective inhibition for beta-galactosidase (Ki = 3.0 x 10(-6) M) and beta-glucosidase (Ki = 1.5 x 10(-7) M), over alpha-galactosidase (Ki = 2.3 x 10(-5) M) and alpha-glucosidase (IC50 = 1.0 x 10(-4) M). There is no observable cross-reactivity with alpha-mannosidase, beta-mannosidase, or alpha-L-fucosidase.     

Design, synthesis, and biological properties of highly potent tubulysin D analogues

Ten analogues of tubulysin D were synthesized and assayed against established mammalian cell lines, including cancer cells measuring inhibition of cell growth by an MTT assay. These experiments establish for the first time the essential features for the potent cytotoxicity of tubulysin D. The activities of analogues 2 to 5 demonstrate that numerous modifications may be introduced at the C-terminus of the natural product with only modest loss in activity, while the activities of analogues 6 to 8 suggest that a basic amine must be present at the N-terminus to maintain activity. Most surprisingly, analogue 10 establishes that replacement of the chemically labile O-acyl N,O-acetal with the stable N-methyl group results in almost no loss in activity. In aggregate, these structure-activity relationships enable the design of analogues such as 11 that are smaller and considerably more stable than tubulysin D but that maintain most of its potent cell-growth inhibitory activity.     

Synthesis of bisubstrate and donor analogues of sialyltransferase and their inhibitory activities

[reaction: see text] Sialyltransferases (STs) are involved in the biosynthesis of glycoconjugates with important biological activities. Most STs utilize cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-Neu5Ac) as a common donor substrate. A bisubstrate analogue containing the donor substrate (CMP-Neu5Ac mimic) and the acceptor substrate (galactose) was synthesized. Four donor analogues having the partial structure of the bisubstrate analogue were also synthesized to support study of the structure-activity relationship. Each analogue contains an ethylene group in place of the exocyclic anomeric oxygen of CMP-Neu5Ac. The bisubstrate analogue exhibited only weak inhibitory activity to rat recombinant alpha-2,3- and alpha-2,6-ST (IC(50) = 1.3, 2.4 mM). Conversion of the C-1 carboxylate of the Neu5Ac moiety to carboxyamide, hydroxymethyl, or methylene phosphate each resulted in a reduction in inhibitory activity. Among the synthesized analogues, cytidin-5'-yl sialylethylphosphonate (4) was the most potent inhibitor against rat recombinant alpha-2,3- and alpha-2,6-ST (IC(50) = 0.047, 0.34 mM).     

Syntheses and bio-activities of the L-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases

(1R)-1-(9-Deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-L-ribitol [(+)-5] and (3S,4S)-1-[(9-deazahypoxanthin-9-yl)methyl]-4-(hydroxymethyl)pyrrolidin-3-ol [(-)-6] are the L-enantiomers of immucillin-H (D-ImmH) and DADMe-immucillin-H (D-DADMe-ImmH), respectively, these D-isomers being high affinity transition state analogue inhibitors of purine nucleoside phosphorylases (PNPases) developed as potential pharmaceuticals against diseases involving irregular activation of T-cells. The C-nucleoside hydrochloride D-ImmH [(-)-5) x HCl], now "Fodosine" is in phase II clinical trials as an anti-T-cell leukaemia agent, while D-DADMe-ImmH is a second generation inhibitor with extreme binding to the target enzyme and has entered the clinic for phase I testing as an anti-psoriasis drug. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the L-nucleoside analogues (+)-5 x HCl and (-)-6, respectively, of D-ImmH and D-DADMe-ImmH, were prepared and their PNPase binding properties were studied. For the synthesis of compound (-)-6 suitable enzyme-based routes to the enantiomerically pure starting material (3S,4S)-4-(hydroxymethyl)pyrrolidin-3-ol [(-)-6] and its enantiomer were developed. The L-enantiomers (+)-5 x HCl and (-)-6 bind to the PNPases approximately 5- to 600-times less well than do the D-compounds, but nevertheless remain powerful inhibitors with nanomolar dissociation constants.     

The Hydrophobicity and Antifungal Potentiation of Burkholdine Analogues

The burkholdines are a family of cyclic lipopeptides reported to exhibit antifungal activity. We synthesized a series of 18 burkholdine analogues in good yield by conventional Fmoc-SPPS followed by cyclization with DIPCI/HOBt in the solution phase. Although none of the synthesized peptides exhibited antifungal activity, several did potentiate the antibiotic effect of the antibiotic G418, including the Thr-bearing Bk analogue (4b) and the tartaramide-bearing Bk analogue (5b). This work exemplifies the potential of burkholdine analogues as potentiating agents.     

Synthesis and antitumor activity of 9-methyl-10-hydroxycamptothecin

A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield was 47.2%. An ether analogue of 4, 9-methyl-10-benzylaminomethoxycamptothecin （5）, was also prepared. These new camptothecin analogues were evaluated for in vitro cytotoxicity against four human cancer cell lines, and exhibited more potent antitumor activities than contrals camptothecin and topotecan against several cancer cells.     

Preparation and antiviral properties of new acyclic, achiral nucleoside analogues: 1- or 9-[3-hydroxy-2-(hydroxymethyl)prop-1-enyl]nucleobases and 1- or 9-[2,3-dihydroxy-2-(hydroxymethyl)propyl]nucleobases

Acyclic, achiral nucleoside derivatives 1b-e of adenine, cytosine, 5-methylcytosine, and guanine, containing a 3-hydroxy-2-(hydroxymethyl)prop-1-enyl group on N-1 or N-9, have been prepared analogously to the previously described thymine derivative 1a. In contrast to the adenine and guanine derivatives, the cytosine derivative 9 was unstable, and was obtained in a low yield due to side reactions. These include cleavage of the propenyl group from the base, and the formation of a bicyclic compound. The thymine derivative, although stable under neutral conditions, likewise underwent a reversible cyclization reaction (Michael addition) in the presence of acids or bases. The 5-methylcytosine derivative was stable under neutral and basic conditions. Four other nucleoside derivatives 26a-d containing a 2,3-dihydroxy-2-(hydroxymethyl)propyl group on N-1 or N-9, three of which are new, have likewise been prepared. All compounds were evaluated as antiviral agents against HIV-1 and HSV-1 but were devoid of antiviral activity.     

Synthesis and evaluation of aminocyclopentitol inhibitors of beta-glucosidases

[reaction: see text] (1R,2S,3S,4R,5R)-4-Amino-5-(hydroxymethyl)cyclopentane-1,2,3-triol 1, prepared from D-glucose, inhibits beta-glucosidases from Caldocellum saccharolyticum (Ki = 1.8 x 10(-7) M) and from almonds (Ki = 3.4 x 10(-6) M). Inhibition is not influenced by N-ethylation (--> 15) but is strongly reduced upon N-acetylation (--> 12). Inversion of stereochemistry at C(5) (--> 14) has little effect on inhibition of beta-glucosidases. These experiments suggest that 1 acts as an analogue of a protonated beta-glucoside.     

Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment

The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5 The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2,5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13, 14, 25 and 26, to the anthranilate esters 16, 17, 27 and 28 using N-(trifluoroacetyl)anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18, 19, 29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.     

A novel method for the synthesis of 9-[[2-hydroxy-1-(aminomethyl)ethoxy]methyl]guanine - a potential antiviral agent

9-[[2-Hydroxy-1-(aminomethyl)ethoxy]methyl]guanine (1a), an amino analogue of 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine (I) which is a potent antiviral agent, has been synthesized $\text{via}$ a multistep-synthesis.     

合成SGLT2抑制剂埃格列净的新方法

以D-(+)-葡萄糖酸内酯为原料,经三甲硅基保护羟基后与5-溴-2-氯-4′-乙氧基二苯甲烷偶联制得(2S,3R,4S,5S,6R)-2-［4-氯-3-(4-乙氧苄基)苯基］-6-(羟甲基)-2-甲氧基四氢-2H-吡喃-3,4,5-三醇（2）; 2经羟基保护、氧化和羟醛缩合等5步反应制得(3S,4S,5R,6S)-3,4,5-三(苄氧基)-6-［4-氯-3-(4-乙氧苄基)苯基］-2-(羟甲基)-6-甲氧基四氢-2H-吡喃-2-甲醛（7）; 7经还原、脱苄同时关环制得埃格列净(1S,2S,3S,4R,5S)-5-［4-氯-3-(4-乙氧苄基)苯基］-1-(羟甲基)-6,8-二氧杂二环［3.2.1］辛烷-2,3,4-三醇,其结构经¹H NMR和LC-MS表征。     

Nucleosides and nucleotides. 186. Synthesis and biological activities of pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety.

Pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety were designed as potential antitumor and/or antiviral agents. Pd (O)-catalyzed reactions of enantiomerically pure (+)-(1R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-1-(ethoxycarbonylo xy)-2- cyclopentene (9) with N3-benzoylthymine and -uracil gave carbocyclic nucleosides 10 and 11. Subsequent Pd (O)-catalyzed reactions of N3-benzoyl-1-[(1R,4S)-4-(ethoxycarbonyloxy)-2-cyclopenten-1- yl]thymine (14) and -uracil (15) with O-benzylhydroxylamine smoothly gave the hydroxyamino-substituted carbocyclic nucleosides 16 and 17. From these nucleosides, the target compounds were prepared after deprotection or further reactions. The 2',3'-didehydro-2',3'-dideoxythymidine (D4T) analogue 20 was the most effective compound, with IC50 values of 27.3 and 34.5 microM against KB and L1210 cells in vitro. Carbocyclic analogues of uridine and cytidine (29 and 32) were less effective than 20 against both cell lines.     

Identification of novel alpha-glucosidase inhibitors by screening libraries based on N- [4-(benzyloxy) benzoyl] alanine derivatives

A library of 72 compounds related to N- [4-(benzyloxy) benzoyl]alanine (I) was synthesized, prepared and screened for alpha-glucosidase inhibitory activity. Four compounds showed potent inhibition, six compounds moderate inhibition, and 16 were weak inhibitors. One compound, N- [4-(benzyloxy) benzoyl] serine, was found to be a potent inhibitor of alpha-glucosidase with 100% inhibition at 1 micro M. This inhibitor was at least five times more potent than the lead compound I.     

Selenium-bridged diiron hexacarbonyl complexes as biomimetic models for the active site of Fe-Fe hydrogenases

Three N-substituted selenium-bridged diiron complexes [{(mu-SeCH2)2NC6H4R}Fe2(CO)6] (R = 4-NO2, 7; R = H, 8; R = 4-CH3, 9) were firstly prepared as biomimetic models for the Fe-Fe hydrogenases active site. Models could be generated by the convergent reaction of [(mu-HSe)2Fe2(CO)6] (6) with N,N-bis(hydroxymethyl)-4-nitroaniline (1), N,N-bis(hydroxymethyl)aniline (2), and N,N-bis(hydroxymethyl)-4-methylaniline (3) in 46-52% yields. All the new complexes were characterized by IR, 1H and 13C NMR and HRMS spectra and their molecular structures were determined by single-crystal X-ray analysis. The redox properties of and their dithiolate analogues [{(mu-SCH2)2NC6H4R}Fe2(CO)6] (R = 4-NO2, 7s; R = H, 8s; R = 4-CH3, 9s ) were evaluated by cyclic voltammograms. The electrochemical proton reduction by and were investigated in the presence of p-toluenesulfonic acid (HOTs) to evaluate the influence of changing the coordinating S atoms of the bridging ligands to Se atoms on the electrocatalytic activity for proton reduction.     

Synthesis of acyclic bis-vinyl pyrimidines: a general route to d4T via metathesis

Unsaturated acyclic pyrimidine analogues, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}uracil, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}thymine and 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}cytosine having two asymmetric carbon atoms have been prepared in good yield starting from uridine and 5-methyluridine. The bis-vinyl thymine derivative underwent ring closure metathesis to give d4T, thus providing a novel synthesis of this compound.     

C-linked galactosyl serine AFGP analogues as potent recrystallization inhibitors

[reaction: see text] A series of C-linked antifreeze glycoprotein analogues have been prepared to evaluate antifreeze activity as a function of distance between the carbohydrate moiety and polypeptide backbone. The building blocks for these analogues were prepared using either an olefin cross-metathesis or catalytic asymmetric hydrogenation. Analysis of antifreeze protein-specific activity revealed that only analogue 2a (n = 1) was a potent recrystallization inhibitor and thus has potential medical and industrial applications.     

Synthesis of N-1-(Indanyloxymethyl) and N-1-(4-Hydroxybut-2-enyloxymethyl) Analogues of the HIV Drugs Emivirine and GCA-186

A series of Emivirine and GCA-186 analogues substituted at N-1 with indan-1-yloxymethyl (6a–6c) and indan-2-yloxymethyl (6d–6f) were synthesized by reaction of the corresponding bis(indanyloxy)methans with uracils having 5-ethyl or 5-isopropyl and 6-benzyl or 6-(3,5-dimethylbenzyl) substituents. A route to the corresponding N-1 substituted 4-hydroxybut-2-enyloxymethyl analogue was also devised. All newly synthesized compounds showed potent activity against wild-type HIV-1, the most active compound being 5-ethyl-1-(indan-1-yloxymethyl)-6-(3,5-dimethylbenzyl)uracil (6b), which was 50-fold more active than Emivirine.     

Synthesis of photoactivatable acyclic analogues of the lobatamides

[structure: see text] The lobatamides and related salicylate enamide natural products are potent mammalian V-ATPase inhibitors. To probe details of binding of the lobatamides to mammalian V-ATPase, three photoactivatable analogues bearing benzophenone photoaffinity labels have been prepared. The analogues were designed on the basis of a simplified acyclic analogue 2. Late-stage installation of the enamide side chain and tandem deallylation/amidation were employed in synthetic routes to these derivatives. Simplified analogue 2 showed strong inhibition against bovine clathrin-coated vesicle V-ATPase (10 nM). Analogues 3-5 were also evaluated for inhibition of bovine V-ATPase in order to select a suitable candidate for future photoaffinity labeling studies.     

4-取代-2,6-二(羟甲基)苯酚的选择氧化

酚类由于本身容易氧化,仅在非常温和的条件下才能直接使4-取代-2,6-二(羟甲基)苯酚中的羟甲基氧化成醛基。文献报道了用活性二氧化锰可以将2,6-二(羟甲基)-4-甲基苯酚氧化成2-羟基-5-甲基-1,3-苯二甲醛,但要使两个羟甲基中只有一个被氧化却是困难的。文献报道了由芳氧基溴化镁与甲醛作用制备水杨醛类化合物的方法,并认为中间产物是邻羟甲基苯酚的镁盐,后者与甲醛之间通过负氢离子转移的分子间氧化还原反应生成相应     

Intercalating nucleic acids (INAs) with insertion of N-(pyren-1-ylmethyl)-(3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol. DNA (RNA) duplex and DNA three-way junction stabilities

N-(Pyren-1-ylmethyl)-(3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol was synthesised from (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol and (3R,4S)-4-[(1S)-1,2-dihydroxyethyl] pyrrolidin-3-ol using alkylation with 1-(chloromethyl)pyrene or reductive amination with pyrene-1-carbaldehyde and NaCNBH3. The incorporation of N-(pyren-1-ylmethyl)azasugar moiety into oligodeoxynucleotides (ODN) as a bulge to form an intercalating nucleic acid (INA) induced a slight destabilization of INA-DNA duplex, whereas the INA-RNA duplex was strongly destabilized and 9 degrees C difference per modification in thermal stability between INA-DNA over INA-RNA duplexes was observed. The stabilization of a DNA three way junction (TWJ) was improved when the intercalator moiety was inserted into the junction region as a bulge.