新型喹唑啉衍生物的设计、合成及体外抗肿瘤活性

为了寻找高效、毒性小的抗肿瘤药物,设计并合成了一系列新型的喹唑啉衍生物,其结构经¹H NMR、 ¹³C NMR、 IR、 MS（ESI）和元素分析表征。采用细胞增殖抑制实验法（MTT法）测定了化合物3a～10c对人盲肠腺癌细胞（HCT-8）、人肝癌细胞（HepG2）、人肺癌细胞（A549） 和人高转移性肝癌细胞（MHCC-97H）的体外抑制活性。结果表明：4-位为氨基苯甲基丙二酸二甲酯时（3a~6c）,化合物的肿瘤抑制作用比其相应水解产物（7a~10c）更强;氨基在苯甲基丙二酸二甲酯间位时,抑制活性明显优于对位取代。其中,5c对HCT-8、 A549及MHCC-97H的抑制活性较显著,IC₅₀值分别为13.613 μmol/L, 13.578 μmol/L和25.804 μmol/L。      

Synthesis and Molecular Docking Studies of Novel 2‐Phenyl‐4‐Substituted Oxazole Derivatives as Potential Anti‐cancer Agents

A novel series of 2,4‐disubstituted oxazole derivatives were synthesized, screened for their anti‐tumor activity against three cell lines MCF‐ 7 , TK‐10, and UACC‐62. Molecular docking study was carried out against epidermal growth factor receptor. A new series of 2‐phenyl‐4‐substituted oxazole derivatives were synthesized. A series of chiral α‐amino acid derivatives 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 were synthesized by coupling various l ‐acylated amino acid azide 3. The synthesized compounds were tested for their in vitro antitumor activity against MCF‐7, TK‐10, and UACC‐62 cell lines. Compound 6 exhibited the strongest inhibitory activity against TK cell lines, while compound 12 showed the highest activity against MCF‐7 cell lines. Compound 14 was the most active against UACC‐62 cell lines. Furthermore, a molecular docking study of the most active compounds was carried out using epidermal growth factor receptor X‐ray 3D structure (protein data bank ID 1 M17). Docking results revealed that compound 6 showed the highest binding energy of ΔG = ?78.17 Kcal/mol.     

Synthesis and Pharmacological Evaluation of 4‐Aryloxyquinazoline Derivatives as Potential Cytotoxic Agents

In the present study, novel 4‐aryloxyquinazoline derivatives were synthesized and screened for in vitro cytotoxicity on human cancer cell lines at 10 μM. Some of the synthesized compounds displayed moderate to significant and selective cytotoxic activity against various leukemia, melanoma, ovarian, breast, and colon cancer cell lines. (E)‐3‐(3,4‐Dimethoxyphenyl)‐1‐(4‐(quinazolin‐4‐yloxy)phenyl)prop‐2‐en‐1‐one ( 9b ) was the most potent compound among all with an average growth inhibition of 70% against leukemia cancer cell lines. The compound also produced strong inhibition (75%) of colon cancer cell lines with 42.58% lethality of HCT‐116 cell line.     

Synthesis and Structure–Activity Relationship Study of Novel Pyrazolylthiazoles as Potential Anti‐Breast Cancer Agents

A novel series of pyrazolylthiazole has been synthesized from the reaction of 5‐(4‐fluorophenyl)‐3‐aryl‐4,5‐dihydropyrazole‐1‐carbothioic acid amide derivatives with different reagents. The mechanism and structures of all the novel products were assured on the foundation of spectral information and elemental analyses. The antitumor activity of all the synthesized compounds was estimated versus MCF‐7 cell line. The outcomes showed that some of the tested samples revealed powerful activity against human breast cancer cell line. In addition, the relation between the structure and the activity has been discussed.     

Synthesis of Novel Quinazoline Derivatives as Antimicrobial Agents

Quinazoline isothiocyanate 1 reacts with various nucleophiles(nitrogen nucleophiles,oxygen nucleophiles and sulphur nucleophiles)to afford heterocyclic systemes 2-13,Also,the [4 2] cycloaddition reaction of 1 with phenyl isocyanate,benzylidene aryl amine and cinnamic acid derivatives gave novel heterocyclic compounds 14-16,Moreover,the reaction of 1 with active methylene compounds under Michael reaction conditions also was investigated to yield 17 and 18 and it was found that all these reactions proceede via isothiocyanate heterocyclization to furnish non-condensed heterocyclic compoundes,Some of the newly synthesized compounds were tested for their antimicrobial activities.     

Synthesis of 2‐(Quinoxalin‐2‐ylamino‐benzotriazolyl) Pentanedioic Derivatives as Potential Anti‐Folate Agents

Anti‐folate agents had a significant impact on therapeutic treatment plans for diseases such as cancer, and bacterial and parasitic infections, notably malaria. Quinoxaline derivatives showed in vitro anticancer activity and were able to inhibit both the dihydrofolate reductase and thymidylate synthase. Here, we decided to combine the chemical properties of quinoxalines and quinoxaline 1,4‐dioxides with those of benzotriazole nucleus with the aim to evaluate the resulting biological properties. Two main new series, including more than 60 compounds, were prepared. In the first one, the benzotriazole moiety was linked through the nitrogen atoms 1, 2, or 3, to a glutaric acid substituent to simulate a glutamic moiety. In the second series, the glutaric acid was substituted with acetic acid moiety to evaluate the effects of steric hindrance. Here, we describe the multistep chemical processes to obtain all titled quinoxalines starting from commercially available diamines. The classical oxidation of selected quinoxalines was unsuccessful, and we have come to an independent synthetic pathway to obtain new derivatives linked to the benzotriazole moieties starting from synthons bearing N‐oxide functionality.     

Synthesis of New Fused Thienopyrimidines Derivatives as Anti‐inflammatory Agents

5‐Amino‐2‐(p‐tolylamino)‐4‐phenylthieno[2,3‐d]pyrimidine‐6‐carbonitrile 9 , which was synthesized by an innovative method, was used as a versatile precursor for synthesizing pyrimido‐thienopyrimidine, triazolopyrimidothienopyrimidine, and pyrimidothienotriazine compounds. Thus, reaction of aminothienopyrimidinecarbonitrile 9 with chloroacetylchloride in dioxane afforded the chloroacetylaminocarbonitrile derivative 10 , which underwent nucleophilic substitution reactions with various primary and secondary amines gave the corresponding N‐alkyl‐(aryl)amino acetamides 11a,b . On the other hand, the reaction of aminocarbonitrile 9 with triethyl orthoformate followed by cyclization with hydrazine yielded an aminoiminopyrimidine derivative 13 . The latter was used as versatile precursor for synthesis of new heterocyclic compounds. The structures of all the new compounds have been established on the basis of their analytical and spectral data (IR, ¹H NMR, ¹³C NMR, and MS). Some of the synthesized compounds were evaluated in vitro for their anti‐inflammatory activity. All the tested compounds exhibited remarkable anti‐inflammatory activity.     

Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti‐Neuroinflammatory Agents for Ischemic Stroke

Benzoxepane derivatives were designed and synthesized, and one hit compound emerged as being effective in vitro with low toxicity. In vivo, this hit compound ameliorated both sickness behavior through anti‐inflammation in LPS‐induced neuroinflammatory mice model and cerebral ischemic injury through anti‐neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing for the hit compound using photoaffinity probes led to identification of PKM2 as the target protein responsible for anti‐inflammatory effect of the hit compound. Furthermore, the hit exhibited an anti‐neuroinflammatory effect in vitro and in vivo by inhibiting PKM2‐mediated glycolysis and NLRP3 activation, indicating PKM2 as a novel target for neuroinflammation and its related brain disorders. This hit compound has a better safety profile compared to shikonin, a reported PKM2 inhibitor, identifying it as a lead compound in targeting PKM2 for the treatment of inflammation‐related diseases.     

Synthesis and Docking Studies of Some 1,2,3‐Benzotriazine‐4‐one Derivatives as Potential Anticancer Agents

Newly synthesized 1,2,3‐benzotriazine‐4‐one derivatives substituted at position‐3 were characterized by various analytical and spectral techniques. The in vitro antitumor activity was evaluated against three different cell lines (liver cells cancer, colorectal cancer, and breast cancer), where compounds 7b , 15 , and 25 showed strong antitumor activity with IC₅₀ ranging from 5.54 to 16.26 μM. In addition, molecular modeling studies using MOE were performed to investigate their binding modes to the C‐Met kinase active site. Docking results demonstrated that all new compounds recognized the active sites of C‐Met kinase and form different types of bonding interactions with key active site amino acid residues.     

Synthesis of Novel Phthalazine Derivatives as Potential Anticancer and Antioxidant Agents Based on 1‐Chloro‐4‐(4‐phenoxyphenyl)phthalazine

A new series of phthalazine derivatives was synthesized from the reaction of 1‐chloro‐4‐(4‐phenoxyphenyl)phthalazine as a reactive starting material with different carbon, nitrogen, oxygen, and sulfur nucleophiles. The structural formulae of all products were confirmed and characterized by elemental analyses and spectral data (IR, ¹H NMR, ¹³C NMR, and mass spectra). Some of the synthesized derivatives were screened for their antitumor activity against four human tumor cell lines using MTT assay. In comparison with doxorubicin as standard drug, compounds 1 , 20 , and 25 showed the most potent cytotoxic effect. In addition, investigation of antioxidant activity revealed that hydrazinylphthalazine 20 has the highest activity.     

Synthesis and Characterization of Some Heteroaromatic Derivatives of 3‐But‐2‐enoyl‐chromen‐2‐one and Their Potential as Anti‐inflammatory Agents

A novel series of chromen‐2‐ones containing pyrazole, isoxazole, oxazine, and thiazine substitutions have been synthesized by reacting 3‐[3‐(4‐chloro‐phenyl)‐acryloyl]‐chromen‐2‐one and 3‐[3‐(3‐methoxy‐phenyl)‐acryloyl]‐chromen‐2‐one with various cyclizing agents such as hydrazine, phenylhydrazine, urea, and thiourea. The structures of all the synthesized compounds were confirmed by the use of IR, ¹H‐NMR, mass spectroscopy, and elemental analysis data. All the newly synthesized compounds were evaluated for their anti‐inflammatory activity at a dose of 100 mg/kg body weight in carrageenan‐induced rat paw edema model. The entire series of the compounds exhibited moderate to good anti‐inflammatory activity, with the percentage inhibition of edema formation ranging from 39.99 to 63.15 against the reference drug ibuprofen (100 mg/kg) that showed 78.96% inhibition at the third hour. Compounds 3a , 3c , and 3d showed good inhibitory activity, whereas compounds 3b , 3e , 3f , and 3j showed moderate inhibitory activity at the third hour.     

Synthesis of Some Newer Analogues of 4‐Hydroxyphenyl Acetic Acid as Potent Anti‐Inflammatory Agents

A series of 1,3,4‐oxadiazole and 1,2,4‐triazole derivatives of 4‐hydroxyphenyl acetic acid have been synthesized and evaluated for their anti‐inflammatory activity by carrageenan induced rat paw edema method. The compounds, which showed good anti‐inflammatory activity, were screened for their ulcerogenic and lipid peroxidation activities.     

Morpholino‐Functionalized and Heteroaryl‐Substituted Titanocene Anti‐Cancer Drugs: Synthesis and Cytotoxicity Studies

From the carbolithiation of 6‐morpholino fulvene ( 3a ) and different ortho‐lithiated heterocycles (furan, thiophene and N‐methylpyrrole), the corresponding lithium cyclopentadienide intermediate ( 4a – c ) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl₄ resulting in morpholino‐functionalised titanocenes 5a – c . When these titanocenes were tested against LLC‐PK cells, the IC₅₀ values obtained were of 58, 63 and 115 μM for titanocenes 5a – c respectively. The most cytotoxic titanocene 5a with an IC₅₀ value of 58 μM is found to be approximately 20 times less cytotoxic than cis‐platin, which showed an IC₅₀ value of 3.3 μM, when tested on the LLC‐PK cell line, and 10 times less cytotoxic than its dimethylamino‐functionalised analogue (Titanocene C , IC₅₀ = 5.5 μM).     

Novel Steroidal (6R)‐Spiro‐1,3,4‐thiadiazoline Derivatives as Anti‐bacterial Agents

Novel steroidal (6R)‐spiro‐1,3,4‐thiadiazoline derivatives have been synthesized by the cyclization of steroidal thiosemicarbazones. Thiosemicarbazones have been synthesized by the reaction of steroidal ketones with thiosemicarbazide. All the compounds have been characterized by IR, ¹H NMR, mass and elemental analyses. The antibacterial activities of these compounds have been first tested in vitro by the disk diffusion assay against two Gram‐positive and two Gram‐negative bacteria, and then the minimum inhibitory concentration (MIC) values have been determined with the reference of standard drug amoxicillin. The results showed that steroidal thiadiazoline derivatives exhibited better antibacterial activity than the steroidal thiosemicarbazone derivatives. Chloro and acetoxy substituents on the 3β‐position of the steroidal thiadiazoline ring increased the anti‐bacterial activity. Among all the compounds, compounds 7 and 8 were found better inhibitors as compared to the respective drug amoxicillin.     

Facile Synthesis of Novel 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one Derivatives as Potential Anticancer Agents

A series of 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 6a – l ) derivatives has been efficiently synthesized by straightforward sequential reactions. Tandem Vilsmeier Hack reaction/cyclization/bromination/Suzuki cross‐coupling reactions were successfully applied to the preparation of title compounds in good‐to‐high yields. In the synthetic sequences, 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehydes ( 2 ) were found to react with ammonium thiocyanate to yield the corresponding 3‐(isothiazol‐5‐yl)‐2H‐chromen‐2‐ones ( 3 ). These derivatives were brominated with N‐bromo succinamide to yield the corresponding regioselective 3‐(4‐bromoisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 4 ). Finally, compound 4 was treated with various phenyl/pyrazole/7H –pyrrolo[2,3‐d]pyrimidinyl boronic acids 5a – l in the presence of K₂CO₃ and Pd catalyst in dimethylformamide to yield the corresponding title derivatives 6a – l . All the synthesized compounds were characterized by analytical and spectral studies. All the final compounds were screened against different cancer cell lines (A549, PC3, SKOV3, and B16F10), and among these compounds, 6b , 6g , 6h , and 6l displayed moderate cytotoxic activity against the tested cell lines.     

An Efficient Synthesis of a (−)‐Physostigmine's Library for Identifying Potential Anti‐Alzheimer's Agents

An efficient route for the synthesis of (?)‐physostigmine analogs 1a – 1g and 2a – 2k is described. Analogs 1a – 1g were synthesized via copper(I)‐catalyzed cycloaddition between the optically pure azide 10 and a variety of alkynes. Similarly, analogs 2a – 2k were prepared through ‘three‐component Huisgen cycloaddition’ using various amines, propargyl bromine, and 10 in H₂O. Facile preparation of 10 via MacMillan's organocatalysis has made it possible to generate a great diversity of natural product‐like compounds that can be screened for anti‐Alzheimer's effects.     

Synthesis and Evaluation of Pyrido[2,3‐d]pyrimidine and 1,8‐Naphthyridine Derivatives as Potential Antitumor Agents

New series of pyrido[2,3‐d]pyrimidine and 1,8‐naphthyridine derivatives were synthesized from 2‐amino‐6‐(phenoxathiin‐2‐yl)‐4‐(thiophene‐2‐yl) nicotinonitrile as starting material, and their structures were characterized on the basis of the spectral data. Most of the synthesized compounds were evaluated for their cytotoxic activity against two cancer cell lines, namely, breast cancer Michigan Cancer Foundation‐7 (MCF‐7) and prostate cancer human prostatic carcinoma cell line (PC‐3) using MTT assay. Some of these compounds showed potent cytotoxic effect concluded from their IC₅₀ values.     

Discovery of Novel Quinazoline Derivatives as Potent Antitumor Agents

In this work, we designed and synthesized a novel series of quinazoline derivatives 6–19 and then evaluated their broad-spectrum antitumor activity against MGC-803, MCF-7, PC-9, A549, and H1975, respectively. Most of them demonstrated low micromolar cytotoxicity towards five tested cell lines. In particular, compound 18 exhibited nanomolar level inhibitory activity against MGC-803 cells with an IC₅₀ value of 0.85 μM, indicating approximately a 32-fold selectivity against GES-1 (IC₅₀ = 26.75 μM). Further preclinical evaluation showed that compound 18 remarkably inhibited the migration of MGC-803 cells, induced cell cycle arrest at G2/M, and induced MGC-803 apoptosis, resulting in decreasing the expression of both Bcl-2 and Mcl-1, and up-regulating the expression of both Bax and cleaved PARP. No death or obvious pathological damage was observed in mice by acute toxicity assay. The in vivo antitumor evaluation suggested that compound 18 significantly decreased the average tumor volume and tumor weight without any effect on body weight, which is better than 5-Fu. Therefore, compound 18 can be used as a lead compound for the further development of antitumor drugs in the future.     

Synthesis and Cytotoxicity of Novel 4′-O-Demethylpodophyllotoxin Derivatives as Potential Anticancer Agents

Chemistry of Natural Compounds - Ten 4β-N-substituted derivatives of 4′-O-demethylpodophyllotoxin were designed by aldehydes reacting with 4′-O-demethylpodophyllotoxin. Their...