Search

Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2-Acetylbenzofuran derivatives 1a,b and 3-acetylindole 1c were condensed with Wittig reagents 2a-d and Wittig-Horner reagents 3a-e to afford the respective 2-ethylidene derivatives 5a-j and 7a-e. Also, iminomethylene triphenylphosphine (2e) reacted with 1a,b to afford benzofuran-2-ylethylidene aniline derivatives 6a,b. In addition, compounds 1a,b reacted with trialkylphosphites 4a-c to give 1:1 adduct for which the Oxaphospholo[4,3-b]benzofuran-7-yl)diazene derivatives 8a-f, were assigned. The possible reactions mechanisms were discussed and structural reasoning for the new compounds were based upon spectroscopic data. Their antiproliferative activities against two cell lines namely, HepG2 and MCF7 cells were then evaluated. It was found that the benzofuran compounds 5b, 6a, and 8c exhibited the strongest antiproliferative activities against both cell lines compared to doxorubicin. By studying the mechanism of action, compound 6a showed good inhibition of tubulin polymerization which leads to mitotic spindle formation disruption, cell cycle arrest in the G2/M phase, and apoptosis of HepG2 cells. A conducted docking study confirmed the in vitro results indicating that compound 6a fitted properly at the colchicine binding site of tubulin. Based on these findings, compound 6a can be considered as a promising anticancer candidate that can be subjected for further development as a tubulin polymerization inhibitor for treating liver and breast cell carcinoma.

Reaction of oxobutenyl- and oxophenylpropenyl-phenylpyrazolones with the active phosphacumulenes, iminovinylidene- and oxovinylidenetriphenylphosphoranes has led to pyranopyrazole and phosphoranylidenepyranopyrazole, respectively. Reaction of the pyrazolones with the stablized phosphonium ylides has resulted in pyrazolodienoates. Reaction of Woolin’s (diselenadiphosphetandiselenides) reagent with the pyrazole derivative substrates has resulted in formation of different phosphorus-selenium heterocyclic pyrazole derivatives such as oxaselenaphosphinin-, selenoxobutenyl-, selenidodiselenaphosphinyl-, and diselenidoselenadiphosphetanylvinyl pyrazoles. The possible reaction mechanism is considered, and structural elucidations are based on spectroscopic data. Antitumor and antioxidant activities of the new compounds have been evaluated. The structure-activity relationship (SAR) for the products is discussed.

Via one-pot reaction of 2-naphthol, thiobarbituric acid and aldehyde in the presence of silica sulfuric acid (SSA) as a catalyst to synthesis benzochromenopyrimidines derivatives. Then we studied the reaction of benzochromenopyrimidines derivatives with bromoacetic acid to obtain benzo[5,6]chromeno[2,3-d]thiazolo[3,2-a]pyrimidine-11,13(10H,14H)-dione derivatives. Meanwhile, dichloroethane was reacted with 12-(4-fluorophenyl)-9-thioxo-9,10-dihydro-8H-benzo[5,6]chromeno[2,3-d]pyrimidin-11(12H)-one to form 14-(4-fluorophenyl)-10,11-dihydrobenzo[5,6]chromeno[2,3-d]thiazolo[3,2-a]pyrimidin-13(14H)-one. All new products structure was elucidated based on analytical and spectroscopic analyses. Anti-cancer activity of newly synthesized structures was investigated. Cancer cells (MDA-MB-231 and HepG2) were used to evaluate the anti-cancer activity of tested compounds using neutral red uptake assay. Treatment of MDA-MB-231 and HepG2 cells with tested compound 6h revealed more inhibitory influence after 48 h. The expression levels of BCL2, BAX, Caspase3, Survivin and P53 genes were investigated using QRT-PCR. This study exhibited that compound 6h revealed significant pro-apoptotic effect via down regulation of BCL2 and Survivin genes and up-regulation of BAX, Caspase3 and P53 genes when treated with MDA-MB-231 and HepG2 cells as compared to control values. The biological studies of these compounds were proved through molecular docking studies with human cyclin-dependent kinase 2 (PDB code: 2A4L) and compound 6h showed low binding energy and shortage bond length with different amino acids. Noteworthy, the tested compound 6h exhibited the most pronounced effect in this respect.

Phosphonium compounds offer an attractive branch of research that chemists and biologists apply for producing many novel drugs for various applications, and its polymeric ingredients are composed of quaternary ammonium and phosphonium salts. The reactions of isothiocyanate with phosphinimine bestow thiaziridine, carbamate, and thiourea derivatives. Moreover, isothiocyanate reacts with tris (dimethylamino) phosphine leading to the formation of sulfidomethyl phosphonium. Lawesson's and Japanese reagents have potential to react with isothiocyanates to generate dithiaphosphetane sulfides. Treatment of isocyanate with Lawesson

5-Amino-2,3-dihydrophthalazine-1,4-dione (Luminol 1) reacted with some organophosphorus reagents such as phosphonium ylides, trialkyl phosphites, and tris(dialkylamino)phosphines to afford the corresponding olefinic products 5a-e, alkoxy-, and dialkylamino derivatives of Luminol 6a-e. 4-Thioxo-3,4-dihydrophthalazin-1(2H)-one derivative 7 was synthesized from the reaction of Luminol (1) with thiating Lawesson and Japanese reagents. Structures of the synthesized compounds were clarified based on their elemental and spectroscopic analyses. The synthesized compounds were evaluated for their antimicrobial activity against some bacterial and fungal strains.

Series of novel sulfonamide-based 3-indolinones 3a-m and 4a-f were designed, synthesized and then their cytotoxic activity was evaluated against a panel of sixty cancer cell lines. This screening indicated that 4-(2-(5-fluoro-2-oxoindolin-3-ylidene)acetyl)phenyl benzenesulfonate (4f) possessed promising cytotoxicity against CCRF-CEM and SR leukemia cell lines with IC50 values 6.84 and 2.97 µM, respectively. Further investigation of the leukemic cytotoxicity of compound 4f was carried out by performing PDGFRα, VEGFR2, Aurora A/B and FLT3 enzyme assays and CCRF-CEM and SR cell cycle analysis. These investigations showed that compound 4f exhibited pronounced dual inhibition of both kinases PDGFRα and Aurora A with potency of 24.15 and 11.83 nM, respectively. The in vitro results were supported by molecular docking studies in order to explore its binding affinity and its key amino acids interactions. This work represents compound 4f as a promising anticancer agent against leukemia.

A green approach for ethylene carbonate ring opening polymerization was proposed via an interaction between ethylene carbonate and 5-azido-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (azidopyrazole) in presence of FeCl3 anhydrous as initiator. Despite the high thermodynamic stability of ethylene carbonate, reducing consumption of heat and time has been obtained. The effect of the molar ratio of azidopyrazole to ethylene carbonate has been studied and the resulted products were characterized.

α-aminophosphonate oxadiazoles (5a-m) were prepared in high yields by reacting of 1,3,4-oxadiazole acetohydrazide (3) with appropriate aldehydes and diethyl phosphite under Kabachnik-Fields conditions using Iron triflate as a catalyst. The reaction conditions were optimized using D-optimal experimental design. Possible reaction mechanisms were considered, and structures of the new products were based upon compatible elementary and spectroscopic evidence. In vitro antitumor activities of these compounds were evaluated against human cancer cell lines of colon (HCT116), breast (MCF7) and liver (HepG2) and compared with anticancer drug, Doxorubicin, employing standard MTT assay. Compounds 5i and 5l demonstrated good antiproliferative activities against HCT116 tumor cells comparable to doxorubicin with low cytotoxicity towards normal fetal colon cell (FHC). Additionally, their capacity to activate apoptosis cascade was studied in HCT116 cell line by investigating the activation of proteolytic caspases cascade, the levels of Cytochrome C, Bax and Bcl-2. Active caspase-3 level was enhanced by 6-8-folds in HCT116 cell line when stimulated with compounds 5i and 5l compared to the control. The level of Caspases 8 & 9 was also increased signifying that intrinsic and extrinsic pathways are both activated. They also induced Bax and down regulated Bcl-2 protein level in addition to over-expressing Cytochrome C level in HCT116 cell line. Also, HCT116 cell cycle was mainly arrested at the Pre-G1 and G2/M phases when treated with compounds 5i and 5l.

A novel series of cyclopent-2-enone derivatives have been synthesised by the reaction of 4-hydroxy-3,4-diphenylcyclopent-2-enone, cyclic secondary amines, phosphorus reagents, hexamethylphosphoramide and Lawesson's reagent in boiling toluene/THF. The chemical structures of new compounds were identified by1H NMR,13C NMR,31P NMR and mass spectra. Furthermore, the structure of one of the synthesised compounds has been confirmed using single crystal X-ray diffraction. The pharmacological evaluation results of antilung and anticolon carcinoma cell line properties for the products are discussed.

The reaction of 1-trimethylsilyl-1 H-imidazole with nucleophilic active phosphacumulenes afforded imidazole silyl phosphoranylidenes or imidazole phosphoranylidenes according to the reaction conditions. The reaction of hexaphenylcarbodiphosphorane with 1-trimethylsilyl-1 H-imidazole resulted in the formation of silyl phosphoranylidene phosphoranyl imidazole, silyl phosphoranylidene imidazole and triphenylphosphane. Moreover, Lawesson and Japanese reagents afforded imidazole phosphinothioic thioanhydrides.

Claisen-Schmidt condensation of ferrocenecarboxaldehyde (2b) with 2-acetylfuran (4) yielded (E)-3-ferrocenyl-1-(2-furyl)prop-2-en-1-one (E -5) together with 1,5-di(2-furyl)-3-ferrocenylpentane-1,5-dione (6). Reactions of the ferrocenyl chalcones 3a,b and 5 with hydrazine hydrate, phenyl hydrazine, ethyl acetoacetate, ethyl cyanoacetate and malononitrile, were also studied. Possible reaction mechanisms were discussed and structures of the new products were unambiguously characterized by common analytical and spectroscopic methods.

1,2-Bis(2-pyridyl)ethane-1,2-dione was allowed to react with different phosphorus nucleophiles. Treatment of the 1,2-bis(2-pyridyl)ethane-1,2-dione with the active phosphacumulene ylides, (N-phenyl...

Phosphazine and phosphazide derivatives are described herein as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and β-amyloid aggregation inhibitors. Phosphazines (5–7) were synthesized smoothly via a redox-condensation reaction of 1,2-bis(diphenylphosphino)ethane with different amines derivatives in the presence of dialkyl azodicarboxylate (Staudinger reaction) while phosphazides (8) via electrophilic attack of azido derivatives. Structures of the synthesized compounds were justified on the basis of compatible elementary and spectroscopic analyses. All the compounds were evaluated for their acetylcholinesterase inhibitory activity. The most three potent compounds (5b-c and 8b) showing AChE IC50 values (29.85–34.96 nM) comparable to that of donepezil (34.42 nM) were subjected to further investigation by testing their butyrylcholinesterase, MMP-2 and self-induced Aβ aggregation inhibition activity. Especially, the coumarin phosphazide derivative (8b) presented the best AChE inhibition selectivity index (IC50 = 34.96 nM, AChE/BuChE; 3.81) together with good inhibition ability against MMP-2 (IC50 = 441.33 nM) and self-induced Aβ1-42 aggregation (IC50 = 337.77 nM). In addition, the inhibition of metal-induced Aβ aggregation by 8b was confirmed by thioflavine T fluorescence. The most potent effect of 8b was observed on the Zn2+-induced Aβ42 aggregation. Kinetic study of compound 8b suggested it to be a competitive AChE inhibitor. Also, it specifically chelates metal and is predicted to be permeable to BBB. It also possesses low toxicity on SH-SY5Y neuroblastoma cells with a safety index of 15.37. In addition, it was demonstrated that compound 8b can improve the cognitive impairment of scopolamine-induced model in mice with % alternations and transfer latency time comparable to that of donepezil. Also, a docking study was carried out and it was in accordance with the in vitro results. These promising in vitro and in vivo findings highlight compound 8b as a possible drug candidate in searching for new multifunctional AD drugs.

New 2-(thiophen-2-yl)-1H-indole derivatives bearing hydrophobic substituents at the 3-position were designed, synthesized and evaluated for their inhibition of HIV-1 reverse transcriptase (RT) enzyme. Dialkylphosphites (2a-c) or trialkylphosphites (3a-c) were reacted with 2-(thiophen-2-yl)-1H-indole-3-carbaldehyde (1) yielding the corresponding α-hydroxyphosphonate adducts (7a-7c). The reaction of compound 1 with the ylidenetriphenylphosphoranes (4a-4c) proceeds via Wittig mechanism giving the corresponding ethylenes (E, 8a-c). Compounds 8b,c were equally obtained upon reacting aldehyde 1 with the appropriate dialkylphosphonates 5a,b under the Horner-Wittig reaction conditions. On the other hand, the reaction of aldehyde 1 with diethyl cyanomethylene phosphonate (5c) yielded a mixture of the E-ethylene 10 and the cyanovinyl phosphonate 11. The thioaldehyde 12 was obtained upon refluxing aldehyde 1 with the Lawesson’s reagent (LR, 6a) or with the Japanese reagent (JR, 6b) in dry toluene. Upon evaluation of HIV-1 Reverse Transcriptase enzyme inhibition, compound 8b (IC50 = 2.93 nM) exhibited the superior HIV-1 RT inhibition and its potency was about 3-folds that of Efavirenz (IC50 = 6.03 nM). Also, compounds 9a (IC50 = 4.09 nM) and 12 (IC50 = 3.54 nM) showed significantly higher inhibition potency. Moreover, compounds 7b (IC50 = 7.48 nM), and 8a (IC50 = 4.55 nM) showed potency not significantly different from that of Efavirenz. Molecular docking experiments on these potent compounds was in accordance with the in vitro data and confirmed binding of these compounds to the enzyme through ring-stacking and hydrogen bond interactions. According to these results, the new molecules would serve as potent HIV-1 NNRTIs inhibitors.

Pyrrolo-pyrazoles were obtained from the reaction between phosphacumulenes and aminoantipyrine, while the reaction with the phosphaallene (hexaphenylcarbodiphosphorane ylide) afforded the azaphosphole and pyrazolo-phosphanylidene. The aminocoumarin carbaldehyde gave the chromeno-phosphanylidene and the chromeno-pyridinone, when it was allowed to react with phosphacumulenes. The reaction of chloroquinoline carbaldehyde with the phosphacumulenes, gave chloroquinoline phosphanylidenecyclobutane, while the reaction with phosphaallene resulted in the formation of oxaphosphetane, phosphanylidene ethenyl- and oxaphosphetyl-quinoline. The structure of cyclobutanedione was confirmed by X-ray crystallography. The antimicrobial activity of the new compounds is also reported.

The reaction of the stabilized phosphonium ylides 2a, 2b with indolinones 1a, 1b and naphthofuranone 13 afforded the corresponding propylidene and ethylidene derivatives 4a, 4b, 4c, 4d and 14a, 14b. On the other hand, the active phosphacumulenes 5a, 5b react with compounds 4a, 4b, 4c, 4d by [4 + 2]-cycloaddition to give the stable phosphanylidene indole pyranones 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h. Although compounds 14a, 14b afforded the naphthofuropyrans 16a, 16b, 16c, 16d and triphenylphosphane. Moreover, the phosphallene ylide 7 react with compounds 4a, 4b, 4c, 4d and 14a, 14b to give phosphanylidenecyclobuteneindoline 9a, 9b, 9c, 9d and naphthalenones 18a, 18b, respectively. In addition, the naphthofuropyridazine 21 was obtained from the reaction of the hydrazone 19 and the phosphacumulene 5a. The antitumor activity of some of the new compounds was evaluated, in vitro, against colon and hepatocellular carcinoma cell lines. They showed values closed to that recorded by the reference drug Doxorubicin.

The reaction of 1-trimethylsilyl-1H-imidazole with nucleophilic active phosphacumulenes afforded imidazole silyl phosphoranylidenes or imidazole phosphoranylidenes according to the reaction conditi...

The reaction of nucleophilic phosphacumulene ylides with visnaginone and khellinone afforded the corresponding phosphanylidene and furochromene derivatives. Moreover, pyranochromenes were obtained from the reaction of chromene carbaldehydes with phosphacumulenes. On the other hand, the phosphanylidene-cyclobutylidenes and their dimers were produced from the reaction of furochromene carbaldehydes with the same phosphonium reagents.

The reaction of Lawesson's reagent 1a, with niclosamide 2 proceeded by thionation and formation of carbothioamide 3 and the zwitterionic oxathiaphosphinin 4a. LR reacted with 8-hydroxyquinoline (5), 2-methylquinoline-4-ol (7), and β-naphthol (9) to give the phosphonodithioates 6, 8, or 10. The reaction of LR with the Mannich bases 11 and 14 afforded the oxathiaphosphinins 13 and 15, whereas the phosphonodithioates 17 and 19 were isolated in the case of Mannich bases 16 and 18. LR reacted with phthalimide Mannich base 20 to give the dithione 21 and N-methylphthalimide (22). Reaction of ketone monoxime 23 with LR resulted in the formation of the oxathiaphosphole 24 and the dithiaphosphole 25, whereas the monoxime 26 afforded the thioxoethanone thioxime 27. Ketone dioximes 28 and 34 afforded the phosphonodithioates 29 and 36, respectively, when they were allowed to react with LR, whereas the dioxime 30 gave compounds 32 and 33. Moreover, the molluscicidal potency of the newly synthesized compounds against Bi...

Reactions of 3-amino-4-aminoximidofurazan (AAOF) with Wittig–Horner reagents, trialkylphosphites, trisdialkylaminophosphines as well as the thiating Lawesson and Japanese reagents were studied. Elemental analysis and spectroscopic measurements were in good accord with the structures postulated for the new products. The antitumor activities of certain selected new compounds were screened, in vitro, against a panel of five (liver; HepG2; breast; MCF-7; lung; A549; colon; HCT116; and prostate PC3) human solid tumor cell lines.

An interesting approach to the synthesis of a variety of new cyclic and heterocyclic phosphorus compounds via direct reaction of readily available indolinones (III) or related naphthofuranone derivatives (IX) with phosphacumulenes (IV) or phosphallene ylide (VI) is given.