Synthesis of new 18-substituted analogues of calcitriol using a photochemical remote functionalization

A novel convergent synthetic approach to new analogues of calcitriol modified at the C-18 position is reported. The key step in the synthesis is the 20-hydroxyl-directed photochemical iodination of the 18-methyl group in the presence of (diacetoxyiodo)benzene. Using this methodology, two new analogues of calcitriol were prepared: the first contains a hydroxylated alkyl side chain attached at C-18 with the natural side chain replaced by an isopropylidene group; the second is a conformationally locked analogue due to an extra oxacycle between the C-18 and C-20 positions.     

Synthesis and antibacterial activity of C-2(S)-substituted pleuromutilin derivatives

<正>In order to probe the effect of C-2(S)-substituted groups in the antibacterial activity,a series of novel C-2(S)-substituted pleuromutilin analogues of SB-225586 were synthesized and evaluated for their in vitro antibacterial activity.The results of antibacterial activities indicated that C-2(S)-substituted pleuromutilin derivatives retained appreciable antibacterial activity,and the 2-fluorination compounds 6a and 6b are more potent than the corresponding 2-hydroxylation analogues 7a and 7b.     

Diverted total synthesis of melodorinol analogues and evaluation of their cytotoxicity

A series of melodorinol analogues were synthesized via a diverted total synthesis approach, leading to structural modifications on several regions of the molecule. Their cytotoxicity was evaluated against five human cancer cell lines (KB, HeLa-S3, MCF-7, HT-29 and A549). Structure-activity relationship studies revealed key parameters that affect the cytotoxicity. In particular, the novel 4-bromo-furanone analogues exhibited greater cytotoxicity compared to the corresponding non-brominated analogues. The stereochemistry at C-6 and the nature of acyl substituents on the C-6 and C-7 hydroxyl groups also play an important role. The most potent analogues exhibit approximately 15-fold higher cytotoxicity towards KB and HeLa-S3 than melodorinol and also show exceptionally high potency against MCF-7, HT-29 and A549 cell lines.     

Synthesis of novel analogues of 1alpha,25-dihydroxyvitamin D(3) with side chains at C-18

Novel analogues of the hormone 1alpha,25-(OH)(2)-D(3) with side chains attached to C-18 were synthesized by a versatile route in which key steps were the remote radical-induced functionalization of the 18-methyl by the C-8beta-hydroxyl group and the introduction of the side chains by Wittig reactions on a C-18-aldehyde. The triene system of the novel analogues was constructed by the convergent Lythgoe-Hoffmann la Roche approach, which involves reaction of a phosphine oxide (the ring A fragment) with a ketone (the upper fragment).     

Conversion of Natural Narciclasine to Its C-1 and C-6 Derivatives and Their Antitumor Activity Evaluation: Some Unusual Chemistry of Narciclasine

During the search for a general, efficient route toward the synthesis of C-1 analogues of narciclasine, natural narciclasine was protected and converted to its C-1 enol derivative using a novel semi-synthetic route. Attempted conversion of this material to its triflate in order to conduct cross-coupling at C-1 resulted in a triflate at C-6 that was successfully coupled with several functionalities. Four novel compounds were fully deprotected after seven steps and subjected to evaluation for cytotoxic activity against three cancer cell lines. Only one derivative showed moderate activity compared to that of narciclasine. Spectral and physical data are provided for all new compounds.     

A novel one-step method for the synthesis of C-5-substituted Omicron6,5'-cyclopyrimidine nucleoside analogues in ammonia water

A novel one-step method for preparing C-5-substituted Omicron(6),5'-cyclopyrimidine nucleoside analogues is reported. This method employs molecular iodine to mediate the cyclization from the 5'-Omicron-hydroxyl group of the sugar ring and C-6 at the position of the nitrogen base in ammonia water under mild conditions without any other aprotic organic solvent.     

Synthesis of novel 1-N-iminosugars from chiral nonracemic bicyclic lactams

This communication reported the synthesis of novel C-6 substituted isofagomine analogues from easily accessible chiral nonracemic bicyclic lactams. These azasugars have potentially very interesting structure and are difficult to obtain by other methods.     

Probing the reactivity of nebularine N1-oxide. A novel approach to C-6 C-substituted purine nucleosides

A novel approach to the synthesis of purine nucleoside analogues, featuring the reaction of the C6-N1-O⁻ aldonitrone moiety of 9-ribosyl-purine (nebularine) N1-oxide with some representative dipolarophiles, as well as Grignard reagents, is reported. Addition of Grignard reagents to the electrophilic C-6 carbon of the substrate allows a facile access to C-6 C-substituted purine nucleosides without using metal catalysts. 1,3-Dipolar cycloaddition processes lead to novel nucleoside analogues via opening, degradation or ring-enlargement of the pyrimidine ring of the base system of the first-formed isoxazoline or isoxazolidine cycloadduct.     

Efficient synthesis and cytotoxicity of novel microtubule-stabilizing agent ceratamine A analogues

An efficient synthesis of microtubule-stabilizing agent ceratamine A analogues is described. The key step is the application of either reductive Heck reaction or Heck reaction to construct the imidazo[4,5-d]azepine core. Thirteen novel analogues of ceratamine A were synthesized and evaluated for their in vitro cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780). It was the first report about the systematic structural modification and SARs study of ceratamine A. The results demonstrated that bulky substituents at C-14 and C-16 could enhance the cytotoxicy and modification at N-7 was crucial for high potency. Especially compound 1f bearing methyl group at C-14 and C-16, and compound 1k bearing benzyl group on N-7, showed better cytotoxicy than ceratamine A against A549.     

Stille/Diels-Alder reaction sequences: diversity-oriented access to novel steroids

[reaction: see text] An efficient, diversity-oriented approach to novel steroid analogues possessing a C-5beta configuration begins with the Stille cross-coupling of enantiomerically pure cycloalkenylstannane trans-2 and enol triflate 3. The resulting diene trans-4 engages in Diels-Alder cycloaddition reactions with a range of dienophiles to give, after removal of protecting groups, biologically interesting 6,7-disubstituted steroid analogues.     

Synthesis and antiviral activity of scopadulcic acids analogues

The synthesis and antiviral properties of several scopadulcic acid analogues functionalized at C-6/C-7 and C-13 is reported. The preparation of advanced intermediates for the synthesis of scopadulcic acid B/scopadulciol analogues is also described. The biological study revealed the importance of polar groups at C-13, while the stereochemistry at C-8 was not critical for activity.     

Efficient synthesis of novel 1alpha-amino and 3beta-amino analogues of 1alpha,25-dihydroxyvitamin d(3)

Convenient synthetic routes to 1alpha-amino-25-hydroxyvitamin D(3) (3) and 3beta-amino-3-deoxy-1alpha,25-dihydroxyvitamin D(3) (4), novel analogues of vitamin D(3) bearing an amino group at the C-1 or C-3 position, have been developed starting from (S)-(+)-carvone. Construction of the A-ring fragments was accomplished by selective enzymatic hydrolysis of a diester intermediate and introduction of the amino group under Mitsunobu conditions.     

Biosynthesis of the beta-amino acid moiety of the enediyne antitumor antibiotic C-1027 featuring beta-amino acyl-S-carrier protein intermediates

The enediyne antitumor antibiotic C-1027 chromoprotein is produced by Streptomyces globisporus. The biosynthesis of the (S)-3-chloro-4,5-dihydroxy-beta-phenylalanine moiety (boxed) of the C-1027 chromophore (1) from l-tyrosine (3) and its incorporation into 1 are catalyzed by six enzymes: SgcC, SgcC1, SgcC2, SgcC3, SgcC4, ShcC5. In vivo and in vitro characterization of these enzymes delineated this pathway, unveiling a novel strategy for beta-amino acid modification featuring beta-amino acyl-S-carrier protein intermediates. These findings shed new light into beta-amino acid biosynthesis and present a new opportunity to engineer the C-1027 biosynthetic machinery for the production of novel analogues as exemplified by 20-deschloro-C-1027 (4), 20-deschro-22-deshydroxy-C-1027 (5), and 22-deshydroxy-C-1027 (6).     

Chemical Strategies towards the Synthesis of Betulinic Acid and Its More Potent Antiprotozoal Analogues

Betulinic acid (BA, 3β-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in Betula ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models—with artesunic acid—showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from Betula ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents.     

Addressing the Structural Complexity of Fluorinated Glucose Analogues: Insight into Lipophilicities and Solvation Effects

In this work, we synthesized all mono-, di-, and trifluorinated glucopyranose analogues at positions C-2, C-3, C-4, and C-6. This systematic investigation allowed us to perform direct comparison of ¹⁹F resonances of fluorinated glucose analogues and also to determine their lipophilicities. Compounds with a fluorine atom at C-6 are usually the most hydrophilic, whereas those with vicinal polyfluorinated motifs are the most lipophilic. Finally, the solvation energies of fluorinated glucose analogues were assessed for the first time by using density functional theory. This method allowed the log P prediction of fluoroglucose analogues, which was comparable to the C log P values obtained from various web-based programs.     

Exploring the hydroxylation-dehydrogenation connection: novel catalytic activity of castor stearoyl-ACP Delta(9) desaturase

The novel product profile obtained by incubating chiral fluorinated substrate analogues with castor stearoyl-ACP Delta(9) desaturase has been rationalized through a series of labeling studies. It was found that the introduction of the Z-double bond between C-9 and C-10 of the parent substrate occurs with pro-R enantioselectivity--a result that accounts for the observed stereochemistry of oxidation products derived from (9R)- and (9S)-9-fluorostearoyl-ACP. Oxidation of (9R)-9-fluorostearoyl-ACP occurs via at least two rapidly interchanging substrate conformations in the active site as detected by reaction pathway branching induced by deuteration at C-10 and C-11. Hydroxylation and desaturation of this substrate share the same site of initial oxidative attack.     

Synthesis of C-15 vindoline analogues by palladium-catalyzed cross-coupling reactions

Described are general protocols for the rapid construction of various C-15-substituted analogues of vindoline using palladium-catalyzed cross-coupling reactions. The required bromo- and iodovindolines were prepared in high yield by the reaction of vindoline with N-bromosuccinimide or N-iodosuccinimide, respectively. The study not only led to the preparation of a number of structurally novel vindoline analogues but also opens the door to new strategies for the synthesis of vinblastine, vincristine, and related anticancer agents. Also described is the conversion of ent-tabersonine to ent-vindoline.     

Semisynthesis of D-ring modified taxoids: novel thia derivatives of docetaxel.

Two novel 5(20)-thia analogues of docetaxel have been synthesized from 10-deacetylbaccatin III or taxine B and isotaxine B. The key step of these syntheses is the concomitant thietane ring formation and acetylation of the tertiary alcohol at C-4. Both compounds are less cytotoxic than docetaxel but have divergent activity on microtubule disassembly.     

Pyridazines. XXXVII. Novel triazanaphthalene derivatives via intramolecular cyclization reactions of vic-disubstituted pyridazines

8-Phenylpyrido[3,4-d]pyridazines bearing various amino substituents at C-5 ( 7a-d, 8 ) were prepared from ethyl 5-benzyl-4-pyridazinecarboxylate 1 via the fused pyridone 5 . The isomeric 4-phenylpyrido[2,3-d]pyridazines having the amino functions attached to C-2 ( 10a-f ) were obtained by a one-pot cyclization of the amino ketone 1 with appropriate acetamide acetals. These novel triazanaphthalene derivatives are of interest as analogues of diuretic and antithrombotic agents.     

Synthesis of proline-modified analogues of the neuroprotective agent glycyl-l-prolyl-glutamic acid (GPE)

The synthesis of ten proline-modified analogues of the neuroprotective tripeptide GPE is described. Five of the analogues incorporate a proline residue with a hydrophobic group at C-2 and two further analogues have this side chain locked into a spirolactam ring system. The pyrrolidine ring was also modified by replacing the γ-CH₂ group with sulfur and/or incorporation of two methyl groups at C-5.