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.     

Synthesis of 10‐amino‐9‐aryl‐2,3,4,5,6,7,9,10‐octahydroacridine‐1,8‐dione derivatives

A series of novel 10‐amino‐9‐aryl‐2,3,4,5,6,7,9,10‐octahydroacridine‐1,8‐dione derivatives 4 were synthesized by hydrazine or phenylhydrazine and 9‐aryl‐1,8‐dioxo‐2,3,4,5,6,7,9‐heptahydroxanthene derivatives 3 , which were prepared by 5‐substituted‐1,3‐cyclohexanedione 1 and aromatic aldehydes 2 in the presence of concentrated H₂SO₄ as a catalyst in water. The structures of all compounds were characterized by IR, MS, ¹H‐NMR, and elemental analysis, and the title compounds possess good fluorescence properties. J. Heterocyclic Chem., (2012).     

Design,Synthesis, and Anticancer Activity of 3H–benzo[f]chromen‐3‐one Derivatives

A series of substituted aminomethylbenzocoumarin derivatives 8a–i have been synthesized, characterized, and structure of compound 8g was confirmed by X‐ray single crystal analysis. All the synthesized compounds were tested for their anticancer activity against cancer cell lines A549 (lung carcinoma cell line), MCF7 (breast cancer cell line), and A375 (melanoma cell line). Compounds 8a , 8f , and 8h showed excellent growth inhibitory activity against all three cell lines, respectively. Compounds 8a and 8f were also found to be quite promising at very low concentration as an anticancer agent against MCF7 and A549 cell lines. Compounds 8g and 8i showed excellent antimitotic activity with IC₅₀ 0.32 and19.98 nM for A549 cell line.     

New Synthetic Approaches for Cytotoxic Activity of Novel 1,8‐Naphthyridine Derivatives

A series of substituted 1,8‐naphthyridine derivatives was synthesized as cytotoxic agent by using starting material 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carbohydrazide ( 1 ). Further reactions on compound 1 were processed with different reagents to afford the corresponding 3‐heteraryl‐1,8‐naphthyridine derivatives 2–22 . In vitro cytotoxic activities of new synthesized compounds were assayed against Ehrlich ascites carcinoma, which showed that compounds 3 and 12 had the more potent cytotoxic activity.     

An Efficient Synthesis of Chromeno[4,3‐d]isoxazolo[5,4‐b]pyridin‐6‐one Derivatives

A series of chromeno[4,3‐d]isoxazolo[5,4‐b]pyridin‐6‐one derivatives were easily and efficiently synthesized by the reaction of 3‐acyl‐2H‐chromen‐2‐ones with isoxazol‐5‐amine in acetic acid. Some synthesized compounds were evaluated for their antiproliferative properties in vitro against cancer cells, and these compounds were found to have some activities.     

Synthesis and Cytotoxic Evaluation of Some 4‐Anilinofuro[2,3‐b]quinoline Derivatives

Some 4‐anilinofuro[2,3‐b]quinoline derivatives were synthesized from dictamnine, a natural alkaloid, and evaluated for their cytotoxicity in the NCI's full panel of 60 human cancer cell lines derived from nine cancer cell types, including leukemia, non‐small‐cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. 1‐[4‐(Furo[2,3‐b]quinolin‐4‐ylamino)phenyl]ethanone ( 5 ) (mean GI₅₀=0.025 μM ), bearing an 4‐acetylanilino substituent at C(4) of furo[2,3‐b]quinoline, was more active than its 3‐acetylanilino counterpart 7 (mean GI₅₀=5.27 μM ), and both clinically used anticancer drugs, N‐[4‐(acridin‐9‐ylamino)‐3‐methoxyphenyl]methanesulfonamide (m‐AMSA; mean GI₅₀=0.44 μM ) and daunomycin (mean GI₅₀=0.044 μM ). Compound 5 was capable of inhibiting all types of cancer cells tested with a mean GI₅₀ of less than 0.04 μM in each case except for the non‐small‐cell lung cancer (average GI₅₀=1.75 μM ). Although non‐small‐cell lung cancer is resistant to compound 5 , the sensitivity within this type of cancer cells varies: HOP‐62 (GI₅₀<0.01 μM ), NCI‐H460 (GI₅₀=0.01 μM ), and NCI‐H522 (GI₅₀<0.01 μM ) are very sensitive, while HOP‐92 (GI₅₀ = 12.4 μM ) is resistant. Among these non‐small‐cell lung cancers, NCI‐H522 was found to be very sensitive to 5, 8a , and 8b with a GI₅₀ values of <0.01, 0.074, and <0.01 μM , respectively.     

Palladium Catalyzed Tricyclohexylphosphine Ligand Associated Synthesis of N‐(2‐(pyridine‐4‐yl)‐1H‐pyrrolo[3,2‐c]‐pyridin‐6‐yl‐(substituted)‐sulfonamide Derivatives as Antiproliferative Agents

A series of novel N‐(2‐(pyridine‐4‐yl)‐1H‐pyrrolo[3,2‐c]‐pyridin‐6‐yl‐(substituted)‐sulfonamide derivatives were synthesized from 2‐bromo‐6‐nitro‐1H‐pyrrolo[3,2‐c]pyridine through a series of reactions including Suzuki reaction, reduction, protection, and sulfonamide coupling. All the synthesized compounds were screened for anticancer activity against MCF‐7, HeLa, A‐549, and Du‐145 cancer cell lines by the MTT assay. The preliminary bioassay suggests that most of the compounds show antiproliferation with different degrees. Doxorubicin was used as a positive control. Among the synthesized compounds, 8d and 8h were most active compared with the standard in cell line data. The synthesized compounds 8d and 8h show IC₅₀ values in the range of 1.88–5.16 μM for all the cell lines. Compounds 8d and 8h were further studied for a panel of eight human kinase at 10 μM concentrations and the result shows 64% to 70% inhibitions for both Aurora‐A and Aurora‐B kinase.     

Synthesis,Anticancer Evaluation,and Molecular Docking Studies of Novel (4‐Hydroxy‐2‐Thioxo‐3,4‐Dihydro‐2H‐[1,3]Thiazin‐6‐Yl)‐Chromen‐2‐Ones via a Multicomponent Approach

A series of coumarin‐substituted 1,3‐thiazine‐2‐thione derivatives ( 4a–m ) were synthesized via the multicomponent reaction of 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehyde ( 1 ) carbon disulfide ( 2 ), and various primary amines ( 3 ), in presence of triethylamine and acetonitrile under stirring with good yields. The structures of all the synthesized compounds were characterized by analytical and spectral studies. Further, the synthesized compounds were screened for their in vitro antiproliferative activities against different cancer cell lines (A549, MDA‐MB‐231, MCF7, HeLa, and B16F10). Studies on the molecular interactions to recognize the hypothetical binding motif of the title compounds with the target Hsp 100 were carried out employing the Schrodinger software. Compounds 4a , 4c and 4m showed activity against all the five cell lines compared with the reference drug, and 4a exhibited the least IC₅₀ concentration of 7.56 ± 1.07 μg/mL against MCF7. This in vitro anticancer result was supported by in silico docking and in silico ADME (absorption, distribution, metabolism, and excretion) studies as well.     

Novel 5‐Methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐ 3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole Derivatives: Synthesis and Anticancer Activity

Eleven novel 5‐methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole derivatives were synthesized and characterized by elemental analysis, ESI‐MS, ¹H NMR and ¹³C NMR. All of the compounds have been screened for their antiproliferative activities against PC‐3 cell (human prostate cancer) and A431 cell (human epidermoid carcinoma cancer) lines in vitro. The results revealed that compounds 4g , 4j and 4k exhibited the strong inhibitory activities against the PC‐3 cell lines (with IC₅₀ values of 2.8±0.11, 3.1±0.10 and 3.0±0.06 μg/mL, respectively).     

Synthesis and Anticancer Evaluation of Some Novel 5‐Amino[1,2,4]Triazole Derivatives

Novel [1,2,4]triazole derivatives were synthesized via various synthetic pathways. Among which were different substituted [1,2,4]triazole analogues that were synthesized, in addition to various fused [1,2,4]triazolo[1,5‐a]pyrimidine derivatives, [1,2,4]triazolo[1,5‐a][1,3,5]triazines, and [1,2,4]triazolo[5,1‐c][1,2,4]triazines. Besides, benzo[h][1,2,4]triazolo[5,1‐b]quinazolines, [1,2,4]triazolo‐[5,1‐b]quinazoline, [1,2,4]triazolo[1,5‐a]quinazoline and [1,2,4]triazolo[5,1‐d][1,2,3,5]tetrazine derivatives were also synthesized. The newly synthesized compounds were evaluated for their in vitro anticancer activity against liver cancer HepG2 and breast cancer MCF7 cell lines compared with the reference drug doxorubicin. Compounds 4 , 7 , 15 , 17 , 28 , 34 , and 47 were found to exert promising anticancer activity against HepG2 cell line showing IC₅₀ values ranging from 17.69 to 25.4 μM/L, while compounds 7 , 14a , 17 , 28 , and 34 showed significant activity against MCF7 cell line with IC₅₀ values ranging from 17.69 to 27.09 μM/L.     

Synthesis and Anticancer Evaluation of Some Novel Thiophene,Thieno[3,2‐d]pyrimidine,Thieno[3,2‐b]pyridine,and Thieno[3,2‐e][1,4]oxazepine Derivatives Containing Benzothiazole Moiety

In an attempt to establish novel candidate with promising anticancer activity, two derivatives of (benzo[d]thiazol‐2‐yl)thiophene backbone 1 and 14 were synthesized, and they further reacted with various chemical reagents to afford the corresponding substituted thiophene derivatives 6 , 8 , 10 , 15 , 17 , and 20 , thieno[3,2‐d]pyrimidine derivatives 2 – 5 , 7 , 9 , 16 , 21 , 23 , and 24 , thieno[3,2‐b]pyridine derivatives 11 – 13 , and thieno[3,2‐e][1,4]oxazepine derivative 18 . Structures of prepared compounds were affirmed via spectral and elemental data. Among the obtained compounds, seven derivatives 2 , 3 , 4 , 5 , 11 , 12 , and 13 were chosen by National Cancer Institute, USA. Such compounds were screened for their antitumor activity versus 60 cancer cell lines in one‐dose (10 μmol) screening assay. The outcomes showed that all selected compounds exhibited moderate to high anticancer activity towards many cancer cell lines among which compounds 5 and 11 exerted potent antitumor activity against numerous malignant growth cell lines particularly Ovarian Cancer IGROV1.     

Synthesis and Antiproliferative Evaluation of New Pyrimido[1,6‐a]Thieno[2,3‐d]Pyrimidine Derivatives

A facile one‐pot synthesis of new pyrimido[1,6‐a ]thieno[2,3‐d ]pyrimidin‐4‐ones 3a , 3b is reported via base‐catalyzed reaction of 2‐amino‐3‐cyanothiophenes 1a , 1b with 2,4‐dichloro‐5‐bromo‐6‐methylpyrimidine 2 . Subsequent treatment of the products with several amines under a mild condition gave a host of the new amino derivatives 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l . The target compounds were evaluated for antiproliferative activity by an 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium assay on human breast cancer (MCF‐7) and mouse fibroblast nonmalignant (L929) cell lines. The activation was structural, concentration, and time dependent. Doses inducing 50% cell‐growth inhibition (IC₅₀) for compounds 3a , 3b and 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l against MCF‐7 cells were explored. Compounds 4f and 4l as the two most potent analogs induced a sub‐G1 peak in the flow‐cytometry histogram of treated cells, compared with control, indicating that apoptotic cell death is involved in compound 4f ‐induced and compound 4l ‐induced toxicity. Compounds 4f and 4l exerted cytotoxic and proapototic effects on MCF‐7 cell line.     

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.     

Synthesis of Some New [1,8]Naphthyridine,Pyrido[2,3‐d]‐Pyrimidine,and Other Annulated Pyridine Derivatives

2‐Aminopyridine‐3‐carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate, benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]naphthyridine derivatives 3 , 5 , 8 , 11 , and 14 , respectively. Further annulations of 3 , 5 , and 8 gave the corresponding pyrido[2,3‐b][1,8]naphthyridine‐3‐carbonitrile derivative 17 , pyrido[2,3‐h][1,6]naphthyridine‐3‐carbonitrile derivatives 18 and 19 , respectively. The reaction of 1 with formic acid, formamide, acetic anhydride, urea or thiourea, and 4‐isothiocyanatobenzenesulfonamide gave the pyridopyrimidine derivatives 20a , b , 21 , 22a , b , and 26 , respectively. Treatment of compound 1 with sulfuric acid afforded the amide derivative 27 . Compound 27 reacted with 4‐chlorobenzaldehyde and 1H‐indene‐1,3(2H)‐dione to give the pyridopyrimidine derivative 28 and spiro derivative 30 , respectively. In addition, compound 1 reacted with halo compounds afforded the pyrrolopyridine derivatives 32 and 34 . Finally, treatment of 1 with hydrazine hydrate gave the pyrazolopyridine derivative 35 . The structures of the newly synthesized compounds were established by elemental and spectral data.     

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 and Bioassay of Novel Substituted Pyrano[2,3‐f]cinnoline‐2‐ones

A new series of 9‐substituted‐4,10‐dimethylpyrano[2,3‐f]cinnolin‐2‐ones ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m ) were synthesized via intramolecular cyclization of the respective acyl amidrazone derivatives ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m ), catalyzed by polyphosphoric acid. Compounds ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m ) were synthesized through direct interaction of coumarin‐7‐yl hydrazonoyl chloride ( 3 ) with the corresponding cyclic sec‐amines in the presence of triethylamine. The structures of the new compounds were confirmed by elemental analyses, NMR, and MS spectral data. The antitumor activity of compounds 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m was evaluated in vitro on breast cancer cell line (MCF‐7) by a cell viability assay utilizing the tetrazolium dye 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide. Among the compounds tested, compounds 5d , 5f , 5k , and 5h showed potential anti‐MCF‐7 activity and were able to reduce the viability after 72 h to less than 50%.     

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.     

Efficient Synthesis of New Thieno[2,3‐d]pyrimidin‐4(3H)‐one Derivatives for Evaluation as Anticancer Agents

Thieno[2,3‐d]pyrimidinones were reported to act as potent anticancer agents; in this work, a series of new substituted thieno[2,3‐d]pyrimidinone ( 6 ) were synthesized via the aza‐Wittig reaction in satisfactory yields. The structures of these compounds were confirmed by elemental analysis, IR, ¹H‐NMR, and mass spectral data, and compound 6h was further analyzed by single crystal X‐ray diffraction. Cytotoxic effect of all the compounds was carried out on human breast and lung cancer cell lines (MCF‐7 and SPC‐A‐1, A459). Compound 6f exhibited the best inhibition activities against A459 with IC₅₀ 4.1 μM.     

Synthesis and Structure of 2‐Substituted Thieno[3′,2′:5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐one Derivatives

A series of new 2‐substituted 3‐(4‐chlorophenyl)‐5,8,9‐trimethylthieno[3′,2′: 5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 8 were synthesized via an aza‐Wittig reaction. Phosphoranylideneamino derivatives 6a or 6b reacted with 4‐chlorophenyl isocyanate to give carbodiimide derivatives 7a or 7b , respectively, which were further treated with amines or phenols to give compounds 8 in the presence of a catalytic amount of EtONa or K₂CO₃. The structure of 2‐(4‐chlorophenoxy)‐3‐(4‐chlorophenyl)‐5,8,9‐trimethylthieno[3′,2′: 5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐one ( 8j ) was comfirmed by X‐ray analysis.     

Synthesis of substituted pyrimido[4,5‐b] and [5,4‐c]‐[1,8]naphthyridines

Ethyl 1‐ethyl‐7‐methyl‐4‐oxo‐1,4‐dihydro[1,8]naphthyridine‐3‐carboxylate ( 1 ), precursor of nalidixic acid, has been converted in two steps through ([1,8]naphthyridin‐3‐yl)carbonylguanidine derivatives into substituted pyrimido[4,5‐b] and [5,4‐c][1,8]naphthyridines.