Synthesis,cytotoxicity, topoisomerase I inhibition and molecular docking of novel phosphoramide mustard sophoridinic acid analogues

A series of novel phosphoramide mustard sophoridinic acid analogues, consisting of nitrogen mustard group and sophoridinic acid scaffold, have been designed, synthesized and evaluated for their topoisomerase inhibitory activity as well as cytotoxicity against six tumor cell lines (SMMC‐7721, LoVo, MCF‐7, K562, S180 and H22) and a normal cell line (L929). Among the compounds tested, five were found to be potent inhibitors and exhibited potent cytotoxicity against S180 and H22 cell lines with IC₅₀ values of 1–4 μM. Further mechanistic studies showed that this class of compounds acted as novel topoisomerase I (Topo I) catalytic inhibitors by preventing the binding of Topo I to DNA and inhibiting the cleavage of DNA, and molecular docking studies revealed that the binding energy for these compounds was comparable to that for classic Topo I inhibitors CPT and HCPT, indicating that the compounds have an interaction with DNA and Topo I.     

Chemometric analysis of metabolism disorders in blood plasma of S180 and H22 tumor‐bearing mice by high performance liquid chromatography‐diode array detection

The aim of this paper is to characterize metabolism disorders in Kunming mice induced by S180 and H22 tumor cells. Metabolic fingerprint based on high performance liquid chromatography‐diode array detector (HPLC‐DAD) was developed to map the disturbed metabolic responses. In vivo testing of the antitumor activity of paclitaxel (Taxol) was carried out by inhibiting the growth of S180 and H22 tumor cells. Based on 27 common peaks, principal component analysis (PCA) and partial least squares‐discriminant analysis (PLS‐DA) were used to distinguish the abnormal from control and to find significant endogenous compounds (SECs) which have significant contributions to classification. The tumor growth inhibition ratios (TIRs) of Taxol groups were used to validate the predictive accuracies of the PLS‐DA models. The predictive accuracies of PLS‐DA models for S180 and H22 tumor model groups were 97.6 and 100%, respectively. Nine (S180) and seven (H22) SECs were discovered, including uric acid and cytidine. In addition, the correlations between relative tumor weights (RTWs) and chromatographic data for the SECs were significant (p < 0.05). Investigations on the stability and precision of the established metabolic fingerprints demonstrate that the experiment is well controlled and reliable. This work shows that the platform of HPLC‐DAD coupled with chemometric methods provides a promising method for the study of metabolism disorders induced by tumor cells. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and antiproliferative evaluation of oxime,methyloxime, and amide‐containing quinazolinones

Certain oxime, methyloxime, and amide‐containing quinazolinone derivatives were synthesized and evaluated in vitro for their antiproliferative activities against a panel of human cancer cell lines including nasopharyngeal carcinoma (NPC‐TW01), lung carcinoma (NCI‐H226), and leukemia (Jurkat). Quinazolinone 2 was inactive against all three cell lines tested, while quinazolinone 4 was weakly active against both Jurkat and H226 cancer cells with IC₅₀ values of 6.55 and 12.27 μM, respectively, indicating that the oxime derivative 4 is more favorable than its ketone precursor 2 . Our results have also indicated that quinazolinone 8g and its biphenyl counterpart 8f exhibited more potent antiproliferative activities than the positive control methotrexate against all three cancer cell lines tested. Among these quinazolinone derivatives, 8g was the most active against NPC‐TW01 with an IC₅₀ value of 4.78 μM. Further study on NPC‐TW01 cell cycle distribution indicated that the compound 8g induced cell arrest at the G1/G0 phase in a time‐ and concentration‐dependent manner. Moreover, a characteristic hypo‐diploid DNA content peak (sub‐G1) was found to increase from 1 to 4% in NPC‐TW01 cells treated with 8g for 72 hr. These results indicate that 8g can induce cells arrest in the G1/G0 phase and cause cell death. Further structural optimization of 8g and detailed study of its antiproliferative mechanism are going on.     

Design,Synthesis, and Evaluation of the Anticancer Properties of a Novel Series of Imidazolone Fused Pyrazolo[1,5‐a]pyrimidine Derivatives

A novel series of imidazolone fused pyrazolo[1,5‐a]pyrimidine derivatives has been designed and synthesized using a convergent approach, and the structures of these compounds were confirmed by ¹H NMR, ¹³C NMR, ESI‐MS, and IR analyses. These new compounds were tested for their in vitro antiproliferative activity using an 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) assay. Out of the 20 derivatives prepared in the current study, compounds 8h , 8n , and 8r exhibited good anticancer activities tested against HeLa cells and HepG₂ cells. However, the in vitro anticancer activity of compound 8r against HeLa, HepG₂, and MCF‐7 cell lines is superior to the marketed drugs Paclitaxel and SAHA.     

Target Visualization by MRI Using the Avidin/Biotin Amplification Route: Synthesis and Testing of a Biotin–Gd‐DOTA Monoamide Trimer

To design efficient targeting strategies in magnetic resonance (MR) molecular imaging applications, the formation of supramolecular adducts between (strept)avidin ((S)Av) and tribiotinylated Gd‐DOTA‐monoamide complexes (DOTA=1,4,7,10‐tetraazacyclododecane‐N,N′,N′′,N′′′‐tetraacetic acid) was explored. Two compounds based on the trivalent core of tris(2‐aminoethyl)amine each containing three biotin molecules and one ( L1 ) or three ( L2 ) DOTA‐monoamide (DOTAMA) ligands were synthesized. In these tribiotinylated derivatives the biotins are spaced far enough apart to allow the formation of the supramolecular adduct with the protein and to host the chelating units in between the (S)Av layers. Size exclusion HPLC analyses indicated complete formation of very high molecular weight polymers (>2 MDa) with (S)Av in solution. A ¹H NMR spectroscopy relaxometric study on the obtained polymeric adducts showed a marked increase of the relaxivity at 35–40 MHz as a consequence of the lengthening of the tumbling time due to the formation of Gd‐chelates/(S)Av polymers. The most efficient Gd₃ L2 /(S)Av polymeric system was used for a test in cell cultures. The target is represented by a neural cell adhesion molecule (NCAM), which is overexpressed in Kaposi’s sarcoma cells and tumor endothelial cells (TEC) and that is efficiently recognized by a biotinylated tetrameric peptide (C3d‐Bio). In vitro experiments showed that only cells incubated with both C3d‐Bio and Gd₃ L2 /SAv polymer were hyperintense with respect to the control. Relaxation rates of cell pellets incubated with Gd₃ L2 /SAv alone were not significantly different from the untreated cells demonstrating the absence of a specific binding.     

The different modes of chiral [1,2,3]triazolo[5,1‐b][1,3,4]thiadiazines: crystal packing,conformation investigation and cellular activity

The crystal structures of four new chiral [1,2,3]triazolo[5,1‐b][1,3,4]thiadiazines are described, namely, ethyl 5′‐benzoyl‐5′H,7′H‐spiro[cyclohexane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate, C₁₉H₂₂N₄O₃S, ethyl 5′‐(4‐methoxybenzoyl)‐5′H,7′H‐spiro[cyclohexane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate, C₂₀H₂₄N₄O₄S, ethyl 6,6‐dimethyl‐5‐(4‐methylbenzoyl)‐6,7‐dihydro‐5H‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine‐3‐carboxylate, C₁₇H₂₀N₄O₃S, and ethyl 5‐benzoyl‐6‐(4‐methoxyphenyl)‐6,7‐dihydro‐5H‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine‐3‐carboxylate, C₂₁H₂₀N₄O₄S. The crystallographic data and cell activities of these four compounds and of the structures of three previously reported similar compounds, namely, ethyl 5′‐(4‐methylbenzoyl)‐5′H,7′H‐spiro[cyclopentane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate, C₁₉H₂₂N₄O₃S, ethyl 5′‐(4‐methoxybenzoyl)‐5′H,7′H‐spiro[cyclopentane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate, C₁₉H₂₂N₄O₄S, and ethyl 6‐methyl‐5‐(4‐methylbenzoyl)‐6‐phenyl‐6,7‐dihydro‐5H‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine‐3‐carboxylate, C₂₂H₂₂N₄O₃S, are contrasted and compared. For both crystallization and an MTT assay, racemic mixtures of the corresponding [1,2,3]triazolo[5,1‐b][1,3,4]thiadiazines were used. The main manner of molecular packing in these compounds is the organization of either enantiomeric pairs or dimers. In both cases, the formation of two three‐centre hydrogen bonds can be detected resulting from intramolecular N—H…O and intermolecular N—H…O or N—H…N interactions. Molecules of different enantiomeric forms can also form chains through N—H…O hydrogen bonds or form layers between which only weak hydrophobic contacts exist. Unlike other [1,2,3]triazolo[5,1‐b][1,3,4]thiadiazines, ethyl 5′‐benzoyl‐5′H,7′H‐spiro[cyclohexane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate contains molecules of only the (R)‐enantiomer; moreover, the N—H group does not participate in any significant intermolecular interactions. Molecular mechanics methods (force field OPLS3e) and the DFT B3LYP/6‐31G+(d,p) method show that the compound forming enantiomeric pairs via weak N—H…N hydrogen bonds is subject to greater distortion of the geometry under the influence of the intermolecular interactions in the crystal. For intramolecular N—H…O and S…O interactions, an analysis of the noncovalent interactions (NCIs) was carried out. The cellular activities of the compounds were tested by evaluating their antiproliferative effect against two normal human cell lines and two cancer cell lines in terms of half‐maximum inhibitory concentration (IC₅₀). Some derivatives have been found to be very effective in inhibiting the growth of Hela cells at nanomolar and submicromolar concentrations with minimal cytotoxicity in relation to normal cells.     

Synthesis and Anti‐tumor Evaluation of Novel C‐37 Modified Derivatives of Gambogic Acid

Gambogic acid (GA, 1 ), the most prominent representative of Garcinia natural products, has been reported to be a promising anti‐tumor agent. In order to further explore the structure‐activity relationship of GA and discover novel GA derivatives as anti‐tumor agents, 17 novel C‐37 modified derivatives of GA were synthesized and evaluated for their in vitro anti‐tumor activities against A549, HCT‐116, BGC‐823, HepG2 and MCF‐7 cancer cell lines. Among them, 11 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 8 was almost 5–10 folds more active than GA against A549 and BGC‐823 cell lines with the IC₅₀ values of 0.12 µmol·L^?1 and 0.57 µmol·L^?1, respectively. Chemical modification at C‐37 position of GA by introducing of hydrophilic amines could lead to increased activity and improved drug‐like properties. These findings will enhance our understanding of the structure‐activity relationship (SAR) of GA and lead to the discovery of novel GA derivatives as potential anti‐tumor agents.     

Synthesis,structural and chemosensitivity studies of arene d6 metal complexes having N‐phenyl‐N´‐(pyridyl/pyrimidyl)thiourea derivatives

The d⁶ metal complexes of thiourea derivatives were synthesized to investigate its cytotoxicity. Treatment of various N‐phenyl‐N´ pyridyl/pyrimidyl thiourea ligands with half‐sandwich d⁶ metal precursors yielded a series of cationic complexes. Reactions of ligand (L1‐L3) with [(p‐cymene)RuCl₂]₂ and [Cp*MCl₂]₂ (M = Rh/Ir) led to the formation of a series of cationic complexes bearing general formula [(arene)M(L1)к²_(N,S)Cl]⁺, [(arene)M(L2)к²_(N,S)Cl]⁺ and [(arene)M(L3)к²_(N,S)Cl]⁺ [arene = p‐cymene, M = Ru ( 1 , 4 , 7 ); Cp*, M = Rh ( 2 , 5 , 8 ); Cp*, Ir ( 3 , 6 , 9 )]. These compounds were isolated as their chloride salts. X‐ray crystallographic studies of the complexes revealed the coordination of the ligands to the metal in a bidentate chelating N,S‐ manner. Further the cytotoxicity studies of the thiourea derivatives and its complexes evaluated against HCT‐116 (human colorectal cancer), MIA‐PaCa‐2 (human pancreatic cancer) and ARPE‐19 (non‐cancer retinal epithelium) cancer cell lines showed that the thiourea ligands displayed no activity. Upon complexation however, the metal compounds possesses cytotoxicity and whilst potency is less than cisplatin, several complexes exhibited greater selectivity for HCT‐116 or MIA‐PaCa‐2 cells compared to ARPE‐19 cells than cisplatin in vitro. Rhodium complexes of thiourea derivatives were found to be more potent as compared to ruthenium and iridium complexes.     

Synthesis and Cytotoxicity Evaluation of Metal‐Chelator‐Bearing Flavone,Carbazole, Dibenzofuran,Xanthone, and Anthraquinone

2‐(Aryloxymethyl)‐5‐benzyloxy‐1‐methyl‐1H‐pyridin‐4‐ones 8a – 8g , 2‐(aryloxymethyl)‐5‐hydroxy‐4H‐pyran‐4‐ones 9a – 9g , and 2‐(aryloxymethyl)‐5‐hydroxy‐1‐methyl‐1H‐pyridin‐4‐ones 10a – 10g were prepared from the known 5‐benzyloxy‐2‐(hydroxymethyl)pyran‐4‐one ( 3 ) in a good overall yield. These compounds were evaluated in vitro against a three‐cell lines panel consisting of MCF7 (breast), NCI‐H460 (lung), and SF‐268 (CNS), and the active compounds passed on for evaluation in the full panel of 60 human tumor cell lines derived from nine cancer cell types. The results indicated that 5‐hydroxy derivatives are more favorable than their corresponding 5‐benzyloxy precursors ( 10a – 10g vs. 8a – 8g ), and 1‐methyl‐1H‐pyridin‐4‐ones are more favorable than their corresponding pyran‐4(1H)‐ones ( 10a – 10g vs. 9a – 9g ). Among these three types of compounds, 2‐(aryloxymethyl)‐5‐hydroxy‐1‐methyl‐1H‐pyridin‐4‐ones 10a – 10g were the most cytotoxic; they inhibited the growth of almost all the cancer cells tested. On the contrary, compound 8a (a mean GI₅₀=27.8 μM ), 8b (38.5), 8d (11.0), and 8e (30.5) are especially active against the growth of SK‐MEL‐5 (a melanoma cancer cell) with a GI₅₀ of <0.01, 5.65, 0.55, and 0.03 μM , respectively (cf. Table 2).     

Synthesis and Antiproliferative Evaluation of 2′‐Arenesulfonyloxy‐5‐benzylidene‐thiazolidine‐2,4‐diones

A series of 2′‐arenesulfonyloxy‐5‐benzylidene‐thiazolidine‐2,4‐diones (TZDs) were synthesized and examined for their antiproliferative effects on a panel of carcinoma cell lines. Our results indicated that initial synthesis of 5‐[2′‐hydroxybenzylidene]‐2,4‐thiazolidinone (9) by Knoevenagel condensation followed by nucleophilic substitution with arylsulfonyl chlorides exhibited superior efficiency to the alternative synthetic route. Among tested compounds, only 8c and 8e showed significant antiproliferative activity against PC‐3 and BT474 cells with GI₅₀ values of 8.4 and 20.6 μM, respectively. SKHep cells displayed interesting structure‐activity relationships in response to TZD derivatives treatment. Alkyl group‐substituted TZD analogs such as 8a (4‐Me, GI₅₀, 9.4 μM) and 8k (4‐iso‐propyl, GI₅₀, 9.8 μM) revealed better antiproliferative activity than those with bulkier alkyl groups. On the other hand, halogen‐substituted TZD analogs 8c, 8h, and 8i showed better antiproliferative activity against H460 cell line. Together, the new synthesized TZD derivatives 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h , 8i , 8j , 8k , 8l , 8m , 8n , 8o , 8p exhibited appreciable antiproliferative activity worth for further study.     

Cathepsin B‐Specific Metabolic Precursor for In Vivo Tumor‐Specific Fluorescence Imaging

Recently, metabolic glycoengineering with bioorthogonal click reactions has focused on improving the tumor targeting efficiency of nanoparticles as delivery vehicles for anticancer drugs or imaging agents. It is the key technique for developing tumor‐specific metabolic precursors that can generate unnatural glycans on the tumor‐cell surface. A cathepsin B‐specific cleavable substrate (KGRR) conjugated with triacetylated N‐azidoacetyl‐d ‐mannosamine (RR‐S‐Ac₃ManNAz) was developed to enable tumor cells to generate unnatural glycans that contain azide groups. The generation of azide groups on the tumor cell surface was exogenously and specifically controlled by the amount of RR‐S‐Ac₃ManNAz that was fed to target tumor cells. Moreover, unnatural glycans on the tumor cell surface were conjugated with near infrared fluorescence (NIRF) dye‐labeled molecules by a bioorthogonal click reaction in cell cultures and in tumor‐bearing mice. Therefore, our RR‐S‐Ac₃ManNAz is promising for research in tumor‐specific imaging or drug delivery.     

甾体磷酰胺类缀合物在电喷雾质谱中的裂解特征

Novel steroidal phosphoramidate conjugates of 3'-azido-2',3'-dideoxythymidine(AZT)and amino acid esterswere synthesized and determined by positive and negative ion electrospray ionization mass spectrometry.The MSfragmentation behaviors of the steroidal phosphoramidate conjugates have been investigated in conjunction withtandem mass spectrometry of ESI-MS/MS.There were three characteristic fragment ions in the positive ion ESImass spectra,which were the Na adduct ions with loss of steroidal moiety,amino acid ester moiety from pseudomolecular ion(M Na)~ ,and the phosphoamino acid methyl ester Na adduct ion by α-cleavage of the phosphora-midate respectively.The main fragment ions in negative ion ESI mass spectra were the ion(M-HN_3)~-,the ion(M-AZT-H)~-,and the ion(M-steroidal moiety-H)~- besides the pseudo molecular ion(M-H)~-.Thefragmentation patterns did not depend on the attached amino acid ester moiety.     

Syntheses and molecular self-assembly of chiral phosphorami-dates

Two chiral phosphoramidates,(R)-(-)-1,1'-binaphthyl-2,2'-dihydroxy-N-[α-(S)-methylbenzyl] phosphoramidate and (-)-1,1'-biphenyl-2,2'-dihydroxy-N-[α-(S)-methylbenzyl]-phosphoramidate were synthesized.Their crystal structures were determined by X-ray single crystal diffraction analysis.The phosphoramidate molecules are self-associated by inter-molecular N-H...O = P hydrogen bonds and aromatic edge to face interactions.     

Synthesis of 4‐Aryl‐8‐fluoro‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolines and Their Ozonides

4‐Aryl‐8‐fluoro‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolines are synthesized by acid‐catalyzed (CF₃CO₂H) three‐component cyclocondensation of 4‐fluoroaniline with aromatic aldehydes and cyclopentadiene. Stable ozonides with (1R*,4S*,5aR*,6S*,11bS*)‐configurations are obtained by ozonolysis of corresponding trifluoroacetyl derivatives.     

Planarity of heteroaryldithiocarbazic acid derivatives showing tuberculostatic activity: structure–activity relationships

The search for new tuberculostatics is an important issue due to the increasing resistance of Mycobacterium tuberculosis to existing agents and the resulting spread of the pathogen. Heteroaryldithiocarbazic acid derivatives have shown potential tuberculostatic activity and investigations of the structural aspects of these compounds are thus of interest. Three new examples have been synthesized. The structure of methyl 2‐[amino(pyridin‐3‐yl)methylidene]hydrazinecarbodithioate, C₈H₁₀N₄S₂, at 293 K has monoclinic (P2₁/n) symmetry. It is of interest with respect to antibacterial properties. The structure displays N—H…N and N—H…S hydrogen bonding. The structure of N′‐(pyrrolidine‐1‐carbonothioyl)picolinohydrazonamide, C₁₁H₁₅N₅S, at 100 K has monoclinic (P2₁/n) symmetry and is also of interest with respect to antibacterial properties. The structure displays N—H…S hydrogen bonding. The structure of (Z)‐methyl 2‐[amino(pyridin‐2‐yl)methylidene]‐1‐methylhydrazinecarbodithioate, C₉H₁₃N₄S₂, has triclinic (P) symmetry. The structure displays N—H…S hydrogen bonding.     

Conformational study of the 3,6‐dihydro‐2H‐1,4‐oxazin‐2‐one fragment in 8‐tert‐butyl‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]decane‐2,10‐dione stereoisomers

Unnatural cyclic α‐amino acids play an important role in the search for biologically active compounds and macromolecules. Enantiomers of natural amino acids with a d configuration are not naturally encoded, but can be chemically synthesized. The crystal structures of two enantiomers obtained by a method of stereoselective synthesis, namely (5R ,8S )‐8‐tert‐butyl‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]decane‐2,10‐dione, (1), and (5S ,8R )‐8‐tert‐butyl‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]decane‐2,10‐dione, (2), both C₁₄H₂₁NO₄, were determined by X‐ray diffraction. Both enantiomers crystallize isostructurally in the space group P 2₁, with one molecule in the asymmetric unit and with the same packing motif. The crystal structures are stabilized by C—H…O hydrogen bonds, resulting in the formation of chains along the [100] and [010] directions. The conformation of the 3,6‐dihydro‐2H‐1,4‐oxazin‐2‐one fragment was compared with other crystal structures possessing this heterocyclic moiety. The comparison showed that the title compounds are not exceptional among structures containing the 3,6‐dihydro‐2H‐1,4‐oxazin‐2‐one fragment. The planar moiety was more frequently observed in derivatives in which this fragment was not condensed with other rings.     

Synthesis of New Fused and Spiro Heterocyclic Systems from 3,5‐Pyrazolidinediones

4‐Bromo‐1‐phenyl‐3,5‐pyrazolidinedione 2 reacted with different nucleophilic reagents to give the corresponding 4‐substituted derivatives 3–8 . The cyclized compounds 9–11 were achieved on refluxing compounds 3 , 4 or 6_a in glacial acetic acid or diphenyl ether. 4,4‐Dibromo‐1‐phenyl‐3,5‐pyrazolidinedione 12 reacted with the proper bidentates to give the corresponding spiro 3,5‐pyrazolidinediones 13–15 , respectively. The 4‐aralkylidine derivatives 16_a‐c , were subjected to Mannich reaction to give Mannich bases 17_a‐c‐22_a‐c , respectively. 4‐(p‐Methylphenylaminomethylidine)‐1‐phenyl‐3,5‐pyrazolidinedione 23 or 4‐(p‐methylphenylazo)‐1‐phenyl‐3,5‐pyrazolidinedione 29 were prepared and reacted with active nitriles, cyclic ketones and N,S‐acetals to give pyrano[2,3‐c]pyrazole, pyrazolo[4′,3′:5,6]pyrano[2,3‐c]pyrazole, spiropyrazole‐4,3′‐pyrazole and spiropyrazole‐4,3′‐[1,2,4]triazolane derivatives 24–34 , respectively.     

Synthesis of Stable Dolichylphosphomannose Analogues

Four oleyl or dolichyl thiophosphate esters 16, 17, 21 , and 22 , analogues of Dol‐P‐Man possessing C(1)? S and/or P? S bonds, were synthesized as potential inhibitors of mannosyl transferases operating in the endoplasmic reticulum (ER). The β‐mannosyl derivatives were prepared by a Mitsunobu reaction of 2,3,4,6‐tetra‐O‐acetyl‐α‐D ‐mannopyranose ( 1 ) with the thiophosphate 2 that provided O‐ and S‐glycosides with good‐to‐excellent diastereoselectivity. A second route to β‐mannosyl derivatives is based on the phosphitylation of the β‐D ‐mannopyranosyl thiol 3 with the phosphoramidites 4a and 4b . Oxidation of the intermediate oleyl thiophosphite with t‐BuOOH led to mono‐ and dithiophosphates. The thiophospholipids 16, 21 , and 22 were inactive as inhibitors of the Man₆(GlcNAc)₂‐PP‐Dol glycolipid elongation.     

Two thiosemicarbazones derived from salicylaldehyde: very specific hydrogen‐bonding interactions of the N—H...S=C type

The molecular structures of two salicylaldehyde thiosemicarbazone derivatives, namely salicylaldehyde 4‐phenylthiosemicarbazone, C₁₄H₁₃N₃OS, (I), and 4‐methoxysalicylaldehyde 4‐phenylthiosemicarbazone, C₁₅H₁₅N₃O₂S, (II), both of potential pharmacological interest, are found in the keto (thione) tautomeric form. The first compound represents a second triclinic polymorph of composition β‐C₁₄H₁₃N₃OS. Although both polymorphs crystallize in the same space group (P), the α‐polymorph [Seena, Kurup & Suresh (2008). J. Chem. Crystallogr. 38 , 93–96] differs from the β form in its unit‐cell volume at 293 K. The molecules in the crystal structures of (I) and (II) are linked into centrosymmetric R²₂(8) dimers by hydrogen bonds of the N—H...S=C type. These dimers are connected through π–π stacking and T‐shaped C—H...π interactions into three‐dimensional networks.     

Ruthenium‐Catalyzed Oxidative Coupling/Cyclization of Isoquinolones with Alkynes through C?H/N?H Activation: Mechanism Study and Synthesis of Dibenzo[a,g]quinolizin‐8‐one Derivatives

The mechanism of [{RuCl₂(p‐cymene)}₂]‐catalyzed oxidative annulations of isoquinolones with alkynes was investigated in detail. The first step is an acetate‐assisted C? H bond activation process to form cyclometalated compounds. Subsequent mono‐alkyne insertion of the Ru? C bonds of the cyclometalated compounds then takes place. Finally, oxidative coupling of the C? N bond of the insertion compounds occurs to afford Ru⁰ sandwich complexes that undergo oxidation to regenerate the catalytically active Ru^II complex with the copper oxidant and release the desired dibenzo[a,g]quinolizin‐8‐one derivatives. All of the relevant intermediates were fully characterized and determined by single crystal X‐ray diffraction analysis. The [{RuCl₂(p‐cymene)}₂]‐catalyzed C? H bond functionalization of isoquinolones with alkynes to synthesize dibenzo[a,g]quinolizin‐8‐one derivatives through C? H/N? H activation was also demonstrated.