A Facile and Efficient Synthesis of 2‐(5‐(4‐Substitutedphenyl)‐4, 5‐dihydro‐3‐phenylpyrazol‐1‐yl)‐6‐Substitutedbenzothiazoles and Their Biological Studies

A series of new 1‐substituted 3, 5‐diarylpyrazolines ( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ) were synthesized in good yield by both conventional and microwave‐assisted synthesis from α, β‐ unsaturated ketones ( 6 , 7 , 8 , 9 ) in n‐butanol and benzothiazole hydrazines ( 2 , 3 , 4 , 5 ). All the new compounds were characterized by IR, NMR, and mass spectral data. The synthesized compounds ( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ) were evaluated for antibacterial and anthelmintic activities. The compounds showed potent anthelmintic activity against earthworm species (Eudrilus eugeniae) and moderate antibacterial activity against bacterial strains such as Gram positive bacteria, Enterococcus faecalis, Staphylococcus aureus, and Bacillus subtilis, and Gram negative bacteria, Escherichia coli and Proteus mirabilis.     

Synthesis and Reactions of Some New Benzo[a]phenothiazine‐3,4‐dione Derivatives

The reaction of 2,3‐dihydro‐2,3‐epoxy‐1,4‐naphthoquinone ( 4 ) with substituted anilines furnished the corresponding benzo[fused]heterocyclic derivatives 5 , 6 , 6a , 6b , 7 , 8 . Furthermore, treatment of benzo[a]phenothiazine derivative 7 with halo compounds, namely, ethyl bromoacetate, phenacyl bromide, dibromoethane, or chloroacetone afforded ether derivatives 11 , 12 , 13 , 14 , respectively. Moreover, the reaction of 11 with o‐substituted aniline gave the corresponding benzo[a]phenothiazin‐5‐one derivatives 15 , 16 , 17 and benzo[d][1,3]oxazin‐4‐one 18 , respectively. Finally, the chromenone derivative 19 was synthesized via the reaction of ester derivative 11 with salicyaldhyde in refluxing pyridine. The newly synthesized compounds were characterized by spectroscopic measurements (IR, ¹H NMR, ¹³C NMR, and mass spectra).     

Quinolone Analogs 14: Synthesis of Antimalarial 1‐Aryl‐3‐(4‐quinolon‐2‐yl)ureas and Related Compounds

The 4‐quinolone‐2‐carbohydrazide 6a was converted into 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas 5a , 5b , 5c , 5d , 5e , 1‐aryl‐3‐(4‐quinolon‐2‐yl)imidazolidine‐2,4‐diones 9a , 9b , and N‐(4‐quinolon‐2‐yl)carbamates 10a , 10b via 4‐quinolone‐2‐carbonylazide 7a . The 4‐methoxyquinoline‐2‐carbohydrazide 6b was also transformed into 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)ureas 11a , 11b , 11c , 11d , 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)imidazolidine‐2,4‐diones 12a , 12b , and N‐(4‐methoxyquinolin‐2‐yl)carbamates 13a , 13b via 4‐methoxyquinoline‐2‐carbonylazide 7b . Some of the 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas 5a , 5b , 5c , 5d , 5e showed the in vitro antimalarial activity to chloroquine‐resistant Plasmodium falciparum, wherein IC₅₀ was 0.93 to 4.00 μM.     

Ferrocenyl,Alkyl, and Aryl‐Pyrido[2,3‐d]Pyrimidines as Vasorelaxant of Smooth Muscle of Rat Aorta via cAMP Conservation Through Phosphodiesterase Inhibition

New pyrido[2,3‐d]pyrimidines 11 , 12 , 13 , and 21 have been synthesized. The vasorelaxant effect on smooth muscle isolated from rat aorta, via PDEs inhibition, of these compounds along with other pyrido[2,3‐d]pyrimidines 14 , 15 , 16 , 17 , 18 , 19 , 20 reported earlier by our group, has also been determined. These pyrido[2,3‐d]pyrimidines 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 were synthesized by the reaction of ferrocenyl‐ethynyl ketones ( 1 , 2 , 3 , 4 ) or α‐alkynyl ketones ( 5 , 6 , 7 , 8 , 9 , 10 ) with 6‐amino‐1,3‐dimethyluracil using [Ni(CN)₄]^?4 as an active catalytic species, formed in situ in a Ni(CN)₂/NaOH/H₂O/CO/KCN aqueous system. Evaluation of the vasorelaxant effect of compounds 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 demonstrated that all compounds relax the tissue in a concentration‐dependent manner. The structural changes do not alter the effectiveness; however, there are differences related to potency expressed as EC₅₀. Compounds 12 (7‐ferrocenyl‐1,3‐dimethyl‐5‐(m‐tolyl)‐pyrido[2,3‐d]pyrimidine) and 13 (7‐ferrocenyl‐1,3‐dipropyl‐5‐(4‐metoxyphenyl)‐pyrido[2,3‐d]pyrimidine) were the most potent compounds, even more than rolipram, reference drug; the EC₅₀ was 0.41 ± 0.02 μM and 0.81 ± 0.11 μM for 12 and 13 , correspondingly. The EC₅₀ of compounds 15 (7‐ferrocenyl‐1,3‐dimethyl‐5‐phenyl‐pyrido[2,3‐d]pyrimidine), 14 (7‐ferrocenyl‐5‐(3,5‐dimethoxyphenyl)‐1,3‐dimethylpyrido[2,3‐d]pyrimidine), and 19 (5‐n‐butyl‐7‐ethyl‐1,3‐dimethylpyrido[2,3‐d]pyrimidine) was similar to EC₅₀ of rolipram. Compounds 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 significantly induce concentration‐dependent vasorelaxation in endothelium‐intact aortic rings. In addition, the relaxation responses to each compound in either endothelium‐intact or endothelium denuded aortic rings were comparable, suggesting that removal of the functional endothelium has no significant influence on its intrinsic vasorelaxant activity. In vitro capability of conserving cyclic‐AMP or cyclic‐GMP (adenosine and guanosine 3′, 5′‐cyclic monophosphate) via PDE inhibition for compounds 12 , 13 , 14 , 15 and 19 was evaluated. Compounds 15 and 19 show the highest percent inhibition effect (94.83% and 83.98%, respectively) for the decomposition of c‐AMP. Docking studies showed that the compound 15 was selective for the inhibition of PDE‐4.     

Sesquiterpenoids from the Fruits of Alpinia oxyphylla and Their Anti‐Acetylcholinesterase Activity

Fourteen sesquiterpenoids were isolated from the fruits of Alpinia oxyphylla Miq . Their structures were elucidated based on NMR analyses (¹H, ¹³C, DEPT, ¹H,¹H‐COSY, HMQC, HMBC, and NOESY) and identified as 12‐nornootkaton‐6‐en‐11‐one ( 3 ), (+)‐(3S,4aS,5R)‐2,3,4,4a,5,6‐hexahydro‐3‐isopropenyl‐4a,5‐dimethyl‐1,7‐naphthoquinone ( 5 ), nootkatene ( 6 ), 9β‐hydroxynootkatone ( 7 ), 2β‐hydroxy‐δ‐cadinol ( 8 ), 4‐isopropyl‐6‐methyl‐1‐tetralone ( 11 ), oxyphyllone E ( 12 ), oxyphyllone D ( 13 ), oxyphyllanene B ( 15 ), oxyphyllone A ( 16 ), oxyphyllol E ( 17 ), (9E)‐humulene‐2,3;6,7‐diepoxide ( 18 ), mustakone ( 20 ), and pubescone ( 21 ). Among them, 3 was a new norsesquiterpenoid, 8 was a new natural product, and 5, 6, 11, 20, 21 were isolated from A. oxyphylla for the first time. Twenty sesquiterpenoids, 1 – 5 and 7 – 21 , were investigated for their in vitro acetylcholinesterase (AChE) inhibitory activities, including previously isolated seven sesquiterpenoids from A. oxyphylla, (11S)‐12‐chloronootkaton‐11‐ol ( 1 ), (11R)‐12‐chloronootkaton‐11‐ol ( 2 ), nootkatone ( 4 ), oxyphyllenodiol A ( 9 ), oxyphyllenodiol B ( 10 ), 7‐epiteucrenone B ( 14 ), and alpinenone ( 19 ). TLC‐Bioautographic assay indicated that 1 – 4, 7, 14, 16, 18, 19 , and 21 displayed anti‐AChE activities at 10 nmol. Microplate assay confirmed that 19, 18, 16 , and 21 displayed moderate‐to‐weak anti‐AChE activities at the concentration of 100 μM , and 19 was the most potent inhibitor with an IC₅₀ value of 81.6±3.5 μM . The presence of anti‐AChE sesquiterpenoids in A. oxyphylla may partially support the traditional use of this fruit for the treatment of dementia.     

2‐Pyrazolin‐5‐One‐Based Heterocycles: Synthesis and Characterization

A novel series of pyrazoline and thiazole derivatives incorporating 2‐pyrazolin‐5‐one moiety were synthesized starting from α,β‐unsaturated ketones under the effect of hydrazine derivatives and thiosemicarbazide. The obtained pyrazolines 4a , 4b were treated with different reagents to afford N‐substituted pyrazolines 5a , 5b , 6a , 6b , 7a , 7b , 8a , 8b . N‐Thiocarbamoyl pyrazolines 12a , 12b were cyclized using phenacyl bromide, 2,3‐dichloroquinoxaline, and monochloroacetic acid afforded the novel pyrazolinyl thiazoles 13a , 13b , 14a , 14b , 15a , 15b , 16a , 16b , 16c , 16d , 16e , 16f . The newly synthesized compounds were characterized by analytical and spectral data.     

Preparation of new N6, 9‐disubstituted 2‐phenyl‐adenines and corresponding 8‐azaadenines.: A feasibility study for application to solid‐phase Synthesis. I

A suitably substituted pyrimidine 1 was converted to a number of title compounds. Nucleophilic substitu tion involving the chlorine atoms in 1 by treatment with phenylmethanethiol yielded 2 or 3 , depending on the reaction temperature. Treatment of 3 with an amine afforded 6‐phenylmethanesulfanyl‐N⁴‐substituted‐2‐phenyl‐pyrimidine‐4,5‐diamines 4–7 . These pyrimidines were converted into 2‐phenylpurines 8–11 and 2‐phenyl‐8‐azapurines 12–14 , by treatment with triethyl orthoformate in the presence of hydrochloric acid (or acetic anhydride), or with potassium nitrite and acetic acid respectively. The thioether function on C(6) was then converted into a sulfonyl group by oxidation with m‐chloroperoxybenzoic acid affording purines 15–18 and their 8‐azaanalogs 19–21 ; these compounds, as crude products, were treated with an amine to yield the corresponding adenines 22–25 or 8‐azaadenines 26–31. All reactions were performed under conditions com patible with the possible use of a thiomethyl resin in place of phenylmethanethiol to bind the pyrimidine ring of 1 to a solid phase.     

Synthesis,PM3‐Semiempirical,and Biological Evaluation of Pyrazolo[4,3‐c]quinolinones

A series of α,β‐unsaturated ketones containing quinolone moieties 2 , 3 , 4 , 5 , 6 were synthesized by condensation of 7‐methoxyquinoline‐2,4(1H,3H)‐dione ( 1 ) with different aryl aldehydes. Pyrazole derivatives 8 , 9 , 10 , 11 were also synthesized via refluxing of α,β‐unsaturated ketones 2 , 3 , 4 , 5 , 6 with hydrazine derivatives. Newly synthesized compounds were characterized by elemental analyses, spectral data, and screened for their antioxidant and antitumor activities. Geometrical optimizations of the molecular structures for different synthesized compounds were studied.     

Study on the reaction of methyl N‐Methyl‐N‐(6‐substituted‐5‐nitropyrimidin‐4‐yl)glycinates with sodium alkoxides

Methyl N‐methyl‐N‐(6‐substituted‐5‐nitropyrimidin‐4‐yl)glycinates ( 4a‐n ), obtained from 6‐substituted‐4‐chloro‐5‐nitropyrimidines and sarcosine methyl ester (methyl 2‐(methylamino)acetate), in the reaction with sodium alkoxides underwent transformations to give different products. N‐methyl‐N‐(5‐nitropyrimidin‐4‐yl)glycinates ( 4a,i,j ) bearing amino and arylamino groups in the position 6 of the pyrimidine ring gave corresponding 6‐substituted‐4‐methylamino‐5‐nitrosopyrimidines ( 5a,i,j ). In the reaction of N‐(6‐alkylamino‐5‐nitropyrimidin‐4‐yl)‐N‐methylglycinates ( 4b,f‐h ) with sodium alkoxides the corresponding 6‐alkylamino‐4‐methylamino‐5‐nitrosopyrimidines ( 5b,f‐h ) and 5‐hydroxy‐8‐methyl‐5,8‐dihydropteridine‐6,7‐diones ( 6b,f‐h ) were formed. The main products of the reaction of N‐(6‐dialkylamino‐5‐nitropyrimidin‐4‐yl)‐N‐methylglycinates ( 4c‐e,k,l ), after work‐up, were the corresponding 6‐dialkylamino‐9‐methylpurin‐8‐ones ( 7c‐e,k,l ) and 8‐alkoxy‐6‐dialkylamino‐9‐methylpurines ( 9c,1,10c,l ). Methyl N‐methyl‐N‐{[6‐(2‐methoxy‐oxoethyl)thio]‐5‐nitropyrimidin‐4‐yl}glycinate ( 4n ) under the same conditions gave methyl 7‐methylaminothiazolo[5,4‐d]pyrimidine‐2‐carboxylate ( 13 ). Mechanisms of the observed transformations are discussed.     

Multiple Pentafluorophenylation of 2,2,3,3,5,6,6‐Heptafluoro‐3,6‐dihydro‐2H‐1,4‐oxazine with an Organosilicon Reagent: NMR and DFT Structural Analysis of Oligo(perfluoroaryl) Compounds

The reagent Me₃Si(C₆F₅) was used for the preparation of a series of perfluorinated, pentafluorophenyl‐substituted 3,6‐dihydro‐2H‐1,4‐oxazines ( 2 – 8 ), which, otherwise, would be very difficult to synthesize. Multiple pentafluorophenylation occurred not only on the heterocyclic ring of the starting compound 1 (Scheme), but also in para position of the introduced C₆F₅ substituent(s) leading to compounds with one to three nonafluorobiphenyl (C₁₂F₉) substituents. While the tris(pentafluorophenyl)‐substituted compound 3 could be isolated as the sole product by stoichiometric control of the reagent, the higher‐substituted compounds 5 – 8 could only be obtained as mixtures. The structures of the oligo(perfluoroaryl) compounds were confirmed by ¹⁹F‐ and ¹³C‐NMR, MS, and/or X‐ray crystallography. DFT simulations of the ¹⁹F‐ and ¹³C‐NMR chemical shifts were performed at the B3LYP‐GIAO/6‐31++G(d,p) level for geometries optimized by the B3LYP/6‐31G(d) level, a technique that proved to be very useful to accomplish full NMR assignment of these complex products.     

Synthesis and In Vitro Antitumor Activity of New Isoxazolo[5,4‐d]Pyrimidine Systems

The reaction of 5‐amino‐3‐methylisoxazole ( 1 ) with aldimines 2 , 3 , 4 , 5 , 6 , 7 gave basic side chain 5‐amino‐3‐methylisoxazole derivatives 8 , 9 , 10 , 11 , 12 , 13 . Annulations of derivatives 8 , 9 , 10 , 11 , 12 , 13 with anisaldehyde afforded the target isoxazolo[5,4‐d]pyrimidines 14 , 15 , 16 , 17 . Treatment of 1 with isatin ketimine anil 18 resulted in the formation of derivative 19 , which further cyclized with anisaldehyde afforded the spirotetracyclic system 20 . Mannich reaction of 1 with primary amine such as methylamine and benzylamine gave the corresponding isoxazolo[5,4‐d]pyrimidine derivatives 21 and 22 , respectively. The newly synthesized compounds were tested for their antitumor activity.     

Palladium‐Catalyzed Cascade Oligocyclizations Involving Competing Elementary Steps Such as Thermal [1,5]‐Acyl Shifts

Palladium(Pd)‐catalyzed oligocyclizations of 2‐bromotetradec‐1‐ene‐7,13‐diynes with an unsubstituted terminal acetylene moiety like 3 and 5 and 15‐bromohexadec‐15‐ene‐3,9‐diyn‐2‐ones like 4 and 6 afforded fulvene derivatives 20 and 21 (Scheme 7) and bis(cyclohexane)‐annulated methylenecyclopentene systems 16 and 18 (Schemes 5 and 6), respectively. These transformations constitute cascades of cyclizing carbopalladation steps with ensuing [1,5]‐sigmatropic H‐atom and acyl shifts, respectively (Scheme 8). In contrast, analogous substrates with one three‐atom and one four‐atom tether between the unsaturated C,C‐bonds, such as 1 and 2 , behave differently in that the Pd‐substituted hexa‐1,3,5‐triene intermediates 12 undergo a 6π‐electrocyclization instead of a 5‐exo‐trig carbopalladation followed by β‐hydride elimination to furnish tricyclic bis‐annulated benzene derivatives 13 and 14 (Scheme 4).     

Oligonucleosides with a Nucleobase‐Including Backbone,Part 3, Synthesis of Acetyleno‐Linked Adenosine Dimers

The adenosine‐derived dimers 14a – d and 15b – d have been prepared by coupling the protected 8‐iodoadenosines 3 and 13 with the C(5′)‐ethynylated adenosine derivatives 5 , 6 , 11 , and 12 (Scheme 4). Similarly, the 5′‐epimeric dimer 16 was prepared by coupling 3 with the alkyne 8 (Scheme 5). The propargylic alcohol 4 was transformed into the N‐benzoylated alkyne 5 and into the amine 6 , while the epimeric alcohol 7 was converted to the epimeric amine 8 and the 5′‐deoxy analogues 11 and 12 (Scheme 3). Cross‐coupling of the iodoadenosine 13 with the alkyne 5 to 14a was optimised; it is influenced by the N‐benzoyl and the Et₃SiO group of the alkyne, but hardly by the N‐benzoyl group of the 8‐iodoadenosine. The alkyne is most reactive when it is O‐silylated, but not N‐benzoylated. Cross‐coupling of the 5′‐deoxyalkynes proceeded more slowly. The dimers 14a – d , 15b – d , and 16 were obtained in good yields (Table 2). Deprotection of 14d and 16 led to 18 and 20 , respectively (Scheme 5). The diols 17 and 19 and the hexols 18 and 20 prefer the syn‐conformation in (D₆)DMSO, completely for unit II and ≥80% for unit I; they exhibit partially persistent intramolecular O(5′)−H⋅⋅⋅N(3) H‐bonds. The persistence increases from 18% (unit I of 19 ), 32% (unit II of 17 and 19 ), 45% (unit I of 17 ), 52% (unit II of 18 and 20 ), and 55% (unit I of 20 ) to 82% (unit I of 18 ).     

One‐pot Synthesis of 1,2,3,4‐Tetrahydropyrimidin‐2(1H)‐thione Derivatives and their Biological Activity

2‐Thioxo/oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate derivatives 2a , 2b , 2c , 2d were prepared by the reaction of ethyl acetoacetate and thiourea or urea with aldehydes using NH₄Cl as a catalyst. Compounds 2a and 2c reacted with mono and bihalogenated compounds such as ethyl iodide, chloroacetonitrile, epichlorohydrin, acetyl chloride, ethyl bromoacetate, chloroacetic acid, chloroacetylchloride, and/or oxalyl chloride to afford compounds 3 , 4a , 4b , 5 , 6a , 6b , 7 , 8 , 9 and 10 , respectively. Compounds 2a , 2c , and 7 were allowed to react with p‐fluorobenzaldehyde to yield the corresponding products 11a , 11b , and 12 , respectively. Oxidation of 2a and 2c gave 2b , 13a , 13b , 14 , 15 , 16 dependent on the oxidizing agent used. Vilsmeiere‐Haack formylation of 2a and 2b with POCl₃/DMF afforded 17a and 17b . Chlorination of 2b and 2d gave the chlorinated derivative 18a and 18b , which reacted with thiourea to give thioureidopyrimidine 19a and 19b . Reactions of 2a with hydrazine monohydrate, semicarbazide hydrochloride, and sodium hydroxide gave compounds 20 , 21 , 22 , respectively. The cytotoxicity and in vitro anticancer evaluation of some prepared compounds have been assessed against two different human tumor cell lines including breast adenocarcinoma MCF‐7 and human hepatocellular carcinoma HepG2. Antimicrobial and antioxidant activities of some compounds were investigated. The newly synthesized compounds were characterized by IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral data.     

Synthesis and Antimicrobial Activities of Novel Series of 3‐(4‐(2‐substituted thiazol‐4‐yl)phenyl)‐2‐(4‐methyl‐2‐substituted thiazol‐5‐yl)thiazolidin‐4‐one Derivatives

In the present investigation, a novel series of 3‐(4‐(2‐substituted thiazol‐4‐yl)phenyl)‐2‐(4‐methyl‐2‐substituted thiazol‐5‐yl)thiazolidin‐4‐one derivatives were synthesized by condensation of 2‐substituted‐4‐methylthiazole‐5‐carbaldehyde with 4‐(2‐substituted thiazol‐4‐yl)benzenamine followed by cyclo‐condensation with thioglycolic acid in toluene. All the newly synthesized compounds were characterized by spectral (IR, ¹H NMR, ¹³C NMR, and Mass) methods. The title compounds were screened for quantitative antibacterial activity (minimal inhibitory concentration). All compounds 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h and 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h show moderate to good antimicrobial activity, whereas compounds ( 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h ) also show moderate antifungal activity.     

Synthesis of 2,4‐disubstituted 6‐phenyl‐7H‐pyrrolo[3,2‐d]‐pyrimidin‐7‐one 5‐oxides

A relatively short and efficient method for the utilization of 4,6‐dichloro‐2‐methylthio‐5‐nitropyrimidine ( 1 ) in the synthesis of the poly substituted pyrrolo[3,2‐d]pyrimidin‐7‐one 5‐oxides ( 6a ‐g) is reported. Some new 4‐substituted 6‐chloro‐2‐methylthio‐5‐nitropyrimidines ( 2a‐e ) were prepared by reaction of 4,6‐dichloro‐2‐methylthio‐5‐nitropyrimidine ( 1 ) with amines. 4‐Substituted 2‐methylthio‐5‐nitro‐6‐phenylethynylpyrimidines ( 3a‐e ), obtained from 4‐substituted 6‐chloro‐2‐methylthio‐5‐nitropyrimidines ( 2a‐e ) via palladium‐catalyzed Sonagashira coupling reaction with 1‐phenylacetylene, underwent smooth cyclization reaction in boiling 2‐propanol in the presence of catalytic amount of pyridine to give 4‐substituted 2‐methylthio‐6‐phenyl‐7H‐pyrrolo[3,2‐d]pyrimidin‐7‐one 5‐oxides ( 4a‐e ). The methylthio group of the latter compounds can be easily and selectively oxidized by m‐chloroperbenzoic acid and replaced with different amines.     

Reactions of Complex Ligands. Part 107 Densely Substituted Hydroquinoid Phenanthrene and Triphenylene Cr(CO)3 Complexes: Chromium‐Templated Synthesis and Molecular Structure

Densely substituted hydroquinoid phenanthrene ( 10 – 18 ), acephenanthrene ( 19 ), and triphenylene chromium tricarbonyl complexes ( 20 – 22 ) have been prepared via benzannulation of naphthalenyl ( 1 – 7 ), acenaphthenyl ( 8 ) and phenanthrenyl carbene complexes ( 9 ), respectively. The naphthalenyl, acenaphthenyl and phenanthrenyl carbene complexes 1 – 9 were obtained in 52–88 % yield starting from commercially available bromoarenes by dehalolithiation, addition of hexacarbonyl chromium to the lithioarene and O‐alkylation of the resulting acyl chromates with trimethyloxonium tetrafluoroborate (Fischer route). The benzannulation of the aryl carbene complexes (either with 3‐hexyne / (t‐butyl)dimethylsilyl chloride or with (t‐butyl)dimethylsilylethyne) allowed the regiospecific synthesis of the oligocyclic hydroquinoid arene tricarbonyl chromium complexes 10 – 22 in 44–94 % yield thus providing a two‐step synthesis with overall yields of 18 ‐ 80 %. Under the kinetic reaction conditions used the metal atom is exclusively coordinated to the persubstituted terminal hydroquinoid ring. The molecular structures of phenanthrene complexes 10 , 12 – 14 , and 16 , acephenanthrene complex 19 , and triphenylene complexes 20 and 21 in the solid state have been determined by X‐ray crystallography. The carbonyl ligands either adopt an eclipsed ( 10 , 12 , 14 , 16 , 19 , 20 ) or staggered ( 13 , 21 ) exo‐conformation pointing away from the center of the phenanthrene, acephenanthrene and triphenylene ligands, respectively. The coordination of the metal atom to the hydroquinoid ring is unsymmetric with the largest metal‐carbon distances found between the chromium atom and one bridgehead carbon and the ring carbon atom bearing the bulky (t‐butyl)dimethylsilyloxy (TBDMSO) substituent.     

Lamellarins as Inhibitors of P‐Glycoprotein‐Mediated Multidrug Resistance in a Human Colon Cancer Cell Line

Chemical analysis of a Didemnum sp. (CMB‐01656) collected during scientific Scuba operations off Wasp Island, New South Wales, yielded five new lamellarins A1 ( 1 ), A2 ( 2 ), A3 ( 3 ), A4 ( 4 ) and A5 ( 5 ) and eight known lamellarins C ( 6 ), E ( 7 ), K ( 8 ), M ( 9 ), S ( 10 ), T ( 11 ), X ( 12 ) and χ ( 13 ). Analysis of a second Didemnum sp. (CMB‐02127) collected during scientific trawling operations along the Northern Rottnest Shelf, Western Australia, yielded the new lamellarin A6 ( 14 ) and two known lamellarins G ( 15 ) and Z ( 16 ). Structures were assigned to 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 on the basis of detailed spectroscopic analysis with comparison to literature data and authentic samples. Access to this unique library of natural lamellarins ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ) provided a rare opportunity for structure–activity relationship (SAR) investigations, probing interactions between lamellarins and the ABC transporter efflux pump P‐glycoprotein (P‐gp) with a view to reversing multidrug resistance in a human colon cancer cell line (SW620 Ad300). These SAR studies, which were expanded to include the permethylated lamellarin derivative ( 17 ) and a series of lamellarin‐inspired synthetic coumarins ( 19 , 20 , 21 , 22 , 23 , 24 ) and isoquinolines ( 25 , 26 ), successfully revealed 17 as a promising new non‐cytotoxic P‐gp inhibitor pharmacophore.     

Synthesis and Bioactivity of Quinoline‐3‐carboxamide Derivatives

Twelve novel substituted 2‐chloroquinoline‐3‐carboxamide derivatives were prepared from acetanilides using the Vilsmeier–Haack reaction, producing 2‐chloro‐3‐carbaldehyde quinolines, followed by oxidation of the 3‐carbaldehyde to the carboxylic acid and coupling this group with various anilines. The structures of the synthesized compounds were confirmed by NMR, mass spectrometry, and single crystal X‐ray diffraction. The chemical shifts of H‐5 and H‐8 were shown to be influenced by the substituent at C‐6. The substituent at C‐6 was also seen to affect the chemical shift of C‐5, C‐7, and C‐8, with C‐5 and C‐7 being more shielded in 5j (F substituted) in comparison with 5g (Cl substituted) and 5d (CH₃ substituted). The compounds showed weak activity in the mM range against Gram‐positive and Gram‐negative bacteria of which 5b , 5d , and 5f showed the best activity with minimum bactericidal concentration values for 5b being 3.79 mM against methicillin‐resistant Staphylococcus aureus and 5d and 5f having minimum bactericidal concentration values of 3.77 and 1.79 mM against S. aureus ATCC 25923, respectively.     

Functionalised Monocyclic Five‐ to Seven‐Membered exo‐Glycals by Alkynol Cycloisomerisation of Hydroxy Buta‐1,3‐diynes and 1‐Haloalkynols

Base‐promoted (KOH or MeONa in MeOH, or NaH in THF) cycloisomerisation of partially benzylated, 1‐substituted (R = Ph CC, pyridin‐2‐yl, or Br) ald‐1‐ynitols leads to (Z)‐configured five‐, six‐, and seven‐membered exo‐glycals. The reactivity of the ald‐1‐ynitols depends upon their configuration. The ald‐1‐ynitols were derived from 2,3,5‐tri‐O‐benzyl‐D ‐ribofuranose 1 , and the corresponding, partially O‐benzylated galactose, glucose, and mannose hemiacetals by ethynylation. The hex‐1‐ynitol 2 derived from 1 (61%) was transformed via the 1‐phenylbuta‐1,3‐diyne 3 and the 1‐(pyridin‐2‐yl)acetylene 5 into the five‐membered exo‐glycals 4 and 6 (in 66 and 72% yields, resp., from 2 ). The analoguous ethynylation of 2,3,4,6‐tetra‐O‐benzyl‐D ‐galactose 8 was accompanied by elimination of one benzyloxy (BnO) group to the hept‐3‐en‐1‐ynitol 9 (71%), which was transformed into the non‐5‐ene‐1,3‐diynitol 10 and further into the six‐membered exo‐glycal 11 (50% from 9 ). Addition of Me₃SiCCH to the galactose 8 and to the gluco‐ and manno‐analogues 16 and 24 gave epimeric mixtures of the silylated oct‐1‐ynitols (86% of 12L / 12D 45 : 55, 94% of 17L / 17D 7 : 3, and 86% of 25L / 25D 55 : 45), which were separated by flash chromatography, and individually transformed into the corresponding 1‐bromooct‐1‐ynitols. Upon treatment with NaH in THF, only the minor epimers 13L, 18D , and 26D cyclised readily to form the seven‐membered hydroxy exo‐glycals. They were acetylated to the more stable monoacetates 14L, 23D , and 28D (82–89% overall yield). Under the same conditions, the epimers 13D, 18L , and 26L decomposed within 12 h mostly to polar products. The difference of reactivity was rationalised by analysing the consequences of an intramolecular C(3)O H ⋅⋅⋅ ⁻OC(7) H‐bond of the intermediate alkoxides on the orientation of ⁻O C(7) of 13L, 18D , and 26D and its proximity to the ethynyl group.