Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

Rational Control of Polyketide Extender Units by Structure‐Based Engineering of a Crotonyl‐CoA Carboxylase/Reductase in Antimycin Biosynthesis

Bioengineering of natural product biosynthesis is a powerful approach to expand the structural diversity of bioactive molecules. However, in polyketide biosynthesis, the modification of polyketide extender units, which form the carbon skeletons, has remained challenging. Herein, we report the rational control of polyketide extender units by the structure‐based engineering of a crotonyl‐CoA carboxylase/reductase (CCR), in the biosynthesis of antimycin. Site‐directed mutagenesis of the CCR enzyme AntE, guided by the crystal structure solved at 1.5 Å resolution, expanded its substrate scope to afford indolylmethylmalonyl‐CoA by the V350G mutation. The mutant A182L selectively catalyzed carboxylation over the regular reduction. Furthermore, the combinatorial biosynthesis of heterocycle‐ and substituted arene‐bearing antimycins was achieved by an engineered Streptomyces strain bearing AntE^V350G. These findings deepen our understanding of the molecular mechanisms of the CCRs, which will serve as versatile biocatalysts for the manipulation of building blocks, and set the stage for the rational design of polyketide biosynthesis.     

Aristolane Sesquiterpenes and Highly Brominated Indoles from the Marine Red Alga Laurencia similis (Rhodomelaceae)

Three new polybrominated 1H‐indoles, compounds 1 – 3 , and three new aristolane sesquiterpenes, compounds 4 – 6 , were isolated from the marine red alga Laurencia similis, together with seven known natural products. Their structures were elucidated on the basis of detailed spectroscopic and mass‐spectrometric analyses, as well as by comparison with literature data.     

Control of the Stereochemical Course of [4+2] Cycloaddition during trans‐Decalin Formation by Fsa2‐Family Enzymes

Enzyme‐catalyzed [4+2] cycloaddition has been proposed to be a key transformation process in various natural product biosynthetic pathways. Recently Fsa2 was found to be involved in stereospecific trans‐decalin formation during the biosynthesis of equisetin, a potent HIV‐1 integrase inhibitor. To understand the mechanisms by which fsa2 determines the stereochemistry of reaction products, we sought an fsa2 homologue that is involved in trans‐decalin formation in the biosynthetic pathway of an enantiomerically opposite analogue, and we found phm7, which is involved in the biosynthesis of phomasetin. A decalin skeleton with an unnatural configuration was successfully constructed by gene replacement of phm7 with fsa2, thus demonstrating enzymatic control of all stereochemistry in the [4+2] cycloaddition. Our findings highlight enzyme‐catalyzed [4+2] cycloaddition as a stereochemically divergent step in natural product biosynthetic pathways and open new avenues for generating derivatives with different stereochemistry.     

Synthesis and Characterization of New (Z)‐5‐((1H‐1,2,4‐Triazol‐1‐yl)methyl)‐3‐arylideneindolin‐2‐ones

Ten compounds of new (Z)‐5‐((1H‐1,24‐triazol‐1‐yl)methyl)‐3‐arylideneindolin‐2‐ones ( 5a – j ) have been synthesized by the Knoevenagel condensation of 5‐((1H‐1,2,4‐triazol‐1‐ylmethyl)indolin‐2‐one ( 3 ) with 4‐substituted aromatic aldehydes ( 4a – j ).     

Synthesis and Antimicrobial Studies of Novel Billogical Heterocycles

The synthetic route of sildenafil promoted us to synthesize new object molecules. New analogues containing a 4-thiazolidinone ring bonded to the phenyl moiety at the 2-position, 7-(substituted anilino)-6-fluoro-2-(p-meth- oxy-m-{[2-(p-hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]aminocarbonyl}phenylsulfonamido)benzothiazoles (4a—4l) have been synthesized by cyclization with thioglycollic acid of Schiff bases 3a—3l from corresponding 7-(substituted anilino)-6-fluoro-2-(p-methoxy-m-hydrazinocarbonyl phenylsulfonamido)benzothiazoles (2a—2l). Compounds 2a—2l in turn were prepared by dehydroxyhalogenation followed by condensation with hydrazine hydrates of acids 1a—1l. Compounds 1a—1l in turn were prepared by chlorosulfonation of o-methoxy benzoic acid followed by condensation with 6-fluoro-7-(substituted anilino)-2-aminobenzothiazoles. Final compounds have been characterized by their elemental analysis, IR, NMR and mass spectra. All the synthesized compounds have been screened for their antimicrobial activities. Some of them showed good activities.     

Structure and Biosynthesis of Isatropolones,Bioactive Amine‐Scavenging Fluorescent Natural Products from Streptomyces Gö66

The natural products isatropolone A–C ( 1 – 3 ) were reisolated from Streptomyces Gö66, with 1 and 3 showing potent activity against Leishmania donovani. They contain a rare tropolone ring derived from a type II polyketide biosynthesis pathway. Their biosynthesis was elucidated by labeling experiments, analysis of the biosynthesis gene cluster, its partial heterologous expression, and structural characterization of various intermediates. Owing to their 1,5‐diketone moiety, they can react with ammonia, amines, lysine, and lysine‐containing peptides and proteins, which results in the formation of a covalent bond and subsequent pyridine ring formation. Their fluorescence properties change upon amine binding, enabling the simple visualization of reacted amines including proteins.     

Isonitrile Formation by a Non‐Heme Iron(II)‐Dependent Oxidase/Decarboxylase

The electron‐rich isonitrile is an important functionality in bioactive natural products, but its biosynthesis has been restricted to the IsnA family of isonitrile synthases. We herein provide the first structural and biochemical evidence of an alternative mechanism for isonitrile formation. ScoE, a putative non‐heme iron(II)‐dependent enzyme from Streptomyces coeruleorubidus, was shown to catalyze the conversion of (R)‐3‐((carboxymethyl)amino)butanoic acid to (R)‐3‐isocyanobutanoic acid through an oxidative decarboxylation mechanism. This work further provides a revised scheme for the biosynthesis of a unique class of isonitrile lipopeptides, of which several members are critical for the virulence of pathogenic mycobacteria.     

Bipolarolides A–G: Ophiobolin‐Derived Sesterterpenes with Three New Carbon Skeletons from Bipolaris sp. TJ403‐B1

Bipolarolides A–G ( 1 – 7 ), seven novel ophiobolin‐derived sesterterpenes with three new types of skeletons, were characterized from fungus Bipolaris sp. TJ403‐B1. Their structures were determined via spectroscopic analyses, X‐ray crystallography, and quantum chemical ¹³C NMR and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were uniquely defined by a multicyclic caged oxapentacyclo[9.3.0.0^1,6.0^5,9.1^8,12]pentadecane‐bridged system. Compounds 3 and 4 featured an unprecedented 5‐5‐5‐5‐fused core skeleton, while 3 also contained an unexpected C‐3–C‐14 oxygen bridge to construct the caged architecture. Compounds 5 – 7 form a new class of highly modified pentacyclic oxaspiro[4.4]nonane‐containing sesterterpene‐alkaloid hybrids. Their biosynthetic pathways and potential HMG‐CoA reductase inhibitory and antimicrobial activities are also discussed.     

Semisynthesis of 3′(2′)‐O‐(Aminoacyl)‐tRNA Derivatives as Ribosomal Substrate

An efficient synthesis of (3′‐terminally) 3′(2′)‐O‐aminoacylated pCpA derivatives is described, which could lead to the production of (aminoacyl)‐tRNAs following T4 RNA ligase mediated ligation. The tetrahydrofuranyl (thf) group was used as a permanent protective group for the 2′‐OH of the cytidine moiety which can be removed during the purification of the 3′(2′)‐O‐aminoacylated‐pCpA. This approach allowed for a general synthesis of (3′‐terminally) 3′(2′)‐O‐aminoacylated oligonucleotides. The fully protected pCpA 14 was synthesized by phosphoramidite chemistry and treated with NH₃ solution to remove the 2‐cyanoethyl and benzoyl groups (→ 15 ; Schemes 1 and 2). The 2′‐O‐thf‐protected‐pCpA 15 was coupled with α‐amino acid cyanomethyl esters, and the products 20a – c were deprotected and purified with AcOH buffer to afford 3′(2′)‐O‐aminoacylated pCpA 21a – c in high yields. The 3′(2′)‐O‐aminoacylated pCpA were efficiently ligated with tRNA(? CA) to yield (aminoacyl)‐tRNA which was an active substrate for the ribosome.     

Synthesis of [3,3′(4H,4′H)‐Bi‐2H‐1,3‐oxazine]‐4,4′‐diones and Their Hydrolysis

The [3,3′(4H,4′H)‐bi‐2H‐1,3‐oxazine]‐4,4′‐diones 3a – 3i were obtained by [2+4] cycloaddition reactions of furan‐2,3‐diones 1a – 1c with aromatic aldazines 2a – 2d (Scheme 1). So, new derivatives of bi‐2H‐1,3‐oxazines and their hydrolysis products, 3,5‐diaryl‐1H‐pyrazoles 4a – 4c (Scheme 3), which are potential biologically active compounds, were synthesized for the first time.     

Synthesis and Microbial Studies of New Pyridine Derivatives-Ill

2-Amino substituted benzothiazole 4a--4I and p-acetamidobenzenesulfonyl chloride 2 were used to prepare 2-（p-aminophenylsulfonamido） substituted benzothiazole 6a--6I using mixture of pyridine and acetic anhydride which formed an electrophilic complex （N-acetyl pyridinium） to facilitate condensation to give desired product by removal of HC1. 2-{p-[（3-Carboxypyrid-2-y1）amino]phenylsulfonamido}benzothiazoles 8a--81 were synthesized from 2-chloropyridine-3-carboxylic acid 7 and 6a--6I in 2-ethoxy ethanol using Cu-powder and K2CO3. Acid chlorides 9a--91 were condensed with 2-hydroxyethyl piperazine 10 and 2,3-dichloropiperazine 11 for amide deriva- tives 2-（p-（（3-（4-（2-hydroxyethy1）piperazin-1-ylcarbonyl）pyrid-2-y1）amino）phenylsulfonamido）benzothiazoes 12a -121 and 2-{p-[3-（2,3-dichloropiperazin-l-ylcarbonyl）pyrid-2-ylamino]phenylsulfonamido}benzothiazoles 13a- 131 respectively. The structures of the new compounds have been established on the basis of their chemical analysis and spectral data （IR, 1↑H NMR and mass）. All the compounds have been screened for their antibacterial and antifungal activities.     

Unprecedented Quassinoids with Promising Biological Activity from Harrisonia perforata

Perforalactone A ( 1 ), a new 20S quassinoid with a unique cagelike 2,4‐dioxaadamantane ring system and a migrated side chain, was isolated from the plant Harrisonia perforata together with two biosynthetically related new quassinoids. The structures of these natural products were elucidated by NMR spectroscopy, X‐ray diffraction analysis, computational modeling, and the CD excitation chirality method. The compounds exhibited notable biological properties, including insecticidal activity against Aphis medicaginis Koch and antagonist activity at the nicotinic acetylcholine receptor of Drosophila melanogaster. The structural features of these compounds may be related to their promising biological characteristics. Their biosynthesis and an alternative origin of quassinoid‐type natural products are also discussed.     

Isolation and Structural Elucidation of Armeniaspirols A–C: Potent Antibiotics against Gram‐Positive Pathogens

In an antibiotic lead discovery program, the known strain Streptomyces armeniacus DSM19369 has been found to produce three new natural products when cultivated on a malt‐containing medium. The challenging structural elucidation of the isolated compounds was achieved by using three independent methods, that is, chemical degradation followed by NMR spectroscopy, a computer‐assisted structure prediction algorithm, and X‐ray crystallography. The compounds, named armeniaspirol A–C ( 2 – 4 ), exhibit a compact, hitherto unprecedented chlorinated spiro[4.4]non‐8‐ene scaffold. Labeling experiments with [1‐¹³C] acetate, [1,2‐¹³C2] acetate, and [U‐¹³C] proline suggest a biosynthesis through a rare two‐chain mechanism. Armeniaspirols displayed moderate to high in vitro activities against Gram‐positive pathogens such as methicillin‐resistant S. aureus (MRSA) or vancomycin resistant E. faecium (VRE). As analogue 2 was active in vivo in an MRSA sepsis model, and showed no development of resistance in a serial passaging experiment, it represents a new antibiotic lead structure.     

Organic Crystals with Near‐Infrared Amplified Spontaneous Emissions Based on 2′‐Hydroxychalcone Derivatives: Subtle Structure Modification but Great Property Change

A series of highly efficient deep red to near‐infrared (NIR) emissive organic crystals 1 – 3 based on the structurally simple 2′‐hydroxychalcone derivatives were synthesized through a simple one‐step condensation reaction. Crystal 1 displays the highest quantum yield (Φ_f) of 0.32 among the reported organic single crystals with an emission maximum (λ_em) over 710 nm. Comparison between the bright emissive crystals 1 – 3 and the nearly nonluminous compounds 4 – 7 clearly gives evidence that a subtle structure modification can arouse great property changes, which is instructive in designing new high‐efficiency organic luminescent materials. Notably, crystals 1 – 3 exhibit amplified spontaneous emissions (ASE) with extremely low thresholds. Thus, organic deep red to NIR emissive crystals with very high Φ_f have been obtained and are found to display the first example of NIR fluorescent crystal ASE.     

Design,Synthesis, and Anticancer Activity of New Oxadiazolyl‐Linked and Thiazolyl‐Linked Benzimidazole Arylidines,Thioglycoside, and Acyclic Analogs

2‐[(4‐Thiazolylmethyl)thio]‐1H‐benzimidazole 3 was prepared and was allowed to react with ethyl chloroactate then with hydrazine hydrate to afford the hydrazide derivative 5 , which was then reacted with aromatic aldehydes to afford the corresponding arylidine derivatives 6 – 9 . Heterocyclization of the latter hydrazones with acetic anhydride afforded the substituted 1,3,4‐oxadiazoline derivatives 10 – 13 . In addition, new ((thiazolyl)imidazolyl) oxadiazole thioglycoside and acyclic‐C nucleoside analog were prepared via heterocylization of the hydrazide 5 then glycosylation with α‐acetobromoglucose or condensation with D‐xylose, respectively. All the new compounds were structurally characterized. The anticancer activity of some of the newly synthesized compounds was studied against human breast cancer cells (MCF‐7). The results of the anticancer activity showed that compounds 8 , 11 , 12 , 17 , and 18 revealed high activities superior to Doxorubicin; however, the other derivatives showed moderate to low inhibition activities against human breast cancer cells. Docking studies into CDK2 enzyme were investigated, which supported the anticancer activity results.     

A Novel Synthesis of 4‐Pyridazineacetic Acids via Ring Expansion of N‐Cyanomethylated 3‐Pyrazoline‐4‐acetic Acids

A novel synthetic route to 4‐pyridazineacetic acids 10 – 12 has been achieved by the ring‐expansion reaction of N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 – 9 . 1H‐Pyrazole‐4‐acetic acids 1 – 3 were reacted with iodoacetonitrile in the presence of triethylamine in refluxing acetonitrile to give the corresponding C‐cyanomethylated 1H‐pyrazole‐4‐acetic acids 4 – 6 as major products together with N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 8 as minor products. On the other hand, reactions of 1 and 3 with chloroacetonitrile in the presence of triethylamine in refluxing chloroform afforded the corresponding N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 9 as major products. Thermal treatment of 7 – 9 with sodium hydride in N,N‐dimethylformamide caused ring expansion to yield the corresponding 4‐pyridazineacetic acids 10 – 12 .     

A Facile Synthesis of Novel (Z)‐ethyl‐3‐(5‐substituted‐1‐alkyl/aryl‐1H‐indol‐3‐yl)‐2‐(1H‐tetrazol‐5‐yl)acrylate

A novel route was developed for synthesis of high potential 1H‐tetrazoles by using conventional method. Tetrazole scaffold is a promising pharmacophore fragment, frequently used in the development of various novel drugs. Here, the novel (Z)‐3‐(N‐alkyl‐indol‐3‐yl)‐2‐(1H‐tetrazole‐5‐yl)acrylates 5 ( a – i ) have been synthesized from (Z)‐ethyl‐3‐(1H‐indol‐3‐yl)2‐(1H‐tetrazol‐5‐yl)acrylates 4 ( a – c ) by using various alkylating agents such as Dimethyl Sulphate (DMS), Diethyl Sulphate (DES), and benzyl chloride; 4 ( a – c ) were synthesized from sodium azide in the presence of copper sulfate in dimethylformamide; 3 ( a – c ) have been prepared by Knoevenagel condensation of indole‐3‐carbaldehyde 1 ( a – c ) and ethylcyanoacetate 2 in the presence of L‐Proline as a catalyst at room temperature in ethanol for an hour. This is an efficient and clean click chemistry method that has various advantages such as easy workup, higher yields, shorter reaction times, and more economical.     

Trangmolins A–F with an Unprecedented Structural Plasticity of the Rings A and B: New Insight into Limonoid Biosynthesis

The absolute stereostructures of trangmolins A–F ( 1 – 6 ), limonoids with three new and one known topologies of the rings A and B, were unambiguously determined by NMR spectroscopic investigations, single‐crystal XRD analysis, and quantum‐chemical electronic circular dichroism calculations. Compounds 1 – 3 contain a hexahydro‐1H‐inden‐4‐one motif, compound 4 comprises a hexahydro‐2,6‐methanobenzofuran‐7‐one cage, and compound 5 consists of a hexahydro‐2H‐2,8‐epoxychromene scaffold. The C1?C30 linkage in 1 – 3 and the C3?C30 connection in 4 form two unprecedented types of ring A/B‐fused carbobicyclic cores: viii and ix . The oxidative cleavage of the C2?C3 bond in 5 and heterocyclization in 4 and 5 constitute the unprecedented tricyclic 6/6/5 ring A/B¹/B²‐ and 6/5/6 ring A¹A²/B‐fused topologies, respectively, which are uncovered, for the first time, in the construction of limonoid architectures. The diverse cyclization patterns of 1 – 6 reveal an unparalleled structural plasticity of rings A and B in limonoid biosynthesis.     

Cuparene‐Derived Sesquiterpenes from the Chinese Red Alga Laurencia okamurai Yamada

Four new cuparene‐derived sesquiterpenes, laureperoxide ( 1 ), 10‐bromoisoaplysin ( 2 ), isodebromolaurinterol ( 3 ), and 10‐hydroxyisolaurene ( 4 ), together with seven known, related sesquiterpenes, 5 – 11 , have been isolated from the red alga Laurencia okamurai. Their structures were determined on the basis of detailed spectroscopic analyses and comparison with known compounds. Compounds 8 – 11 were shown for the first time to represent true natural products, and the full ¹H‐ and ¹³C‐NMR assignments of 5 are reported for the first time.