Synthesis of some 5-arylidene-2-(4-acetamidophenylimino)-thiazolidin-4-one derivatives and exploring their breast anticancer activity

Ten 2-(4-acetamidophenylimino)-5-arylidenethiazolidin-4-one derivatives 6a-k were synthesized and evaluated for their anticancer activity against MCF-7 cell line (breast adenocarcinoma). The synthetic approach involves cyclocondensation of N,N′-bis(4-acetamidophenyl)-thiourea (3) with ethyl bromoacetate in ethanol and sodium acetate to furnish the 2-(4-acetamidophenylimino)-4-thiazolidinone derivative 4 , which underwent Knoevenagel condensation reaction with some substituted aldehydes to afford the targeted 2-(4-acetamidophenylimino)-5-arylidenethiazolidin-4-ones 6a - k . The 4-chlorobenzylidene-thiazolidin-4-one compound 6h exhibited strong inhibitory effect on the growth of breast cancer cell with IC₅₀ (58.33 ± 1.74μM), very close to that of the reference drug doxorubicin (IC₅₀ 48.06 ± 0.36μM).     

Design,synthesis and biological evaluation of some novel <Emphasis Type="Italic">N</Emphasis>-arylpyrazole derivatives bearing the sulfonamide moiety as cytotoxic agents

A series of novel N-arylpyrazole derivatives (4a–4l) bearing the sulfonamide moiety were synthesized by the condensation reaction of 1,3-dicarbonyl compounds with 4-hydrazinylbenzenesulfonamide. The structures of the obtained compounds were established on the basis of elemental (C, H, and N) and spectral analysis (¹H NMR, ¹³C NMR, ESIMS, and FT-IR). These compounds were tested for their in vitro cytotoxic activity against three human tumor cell lines: MCF-7, Hela, and A549. The results showed that most of the obtained compounds exhibited promising cytotoxicity against the tested cell lines with low IC₅₀ values. The pyrazole derivative 4k, bearing two methoxy groups on the 3-position and 4-position of the phenyl ring, was the most effective one. Its inhibition of cell growth of MCF-7 cells was better than that of celecoxib and cisplatin.     

Synthesis of (1′S*,2R*,3R*)- and (1′S*,2R*,3S*)-N-arylsulfonyl-2-(1′-halogenethyl)-3-methylindolines and their selective toxicity against SH-SY5Y cell line

N-tosyl-2- and N-tosyl-4-halogen-substituted derivatives of 2-(1-methylbut-2-en-1-yl)aniline were synthesized and their molecular iodine-mediated cyclization was investigated. The cyclization upon interaction of N-tosyl-6-methyl-2-(1-methylbut-2-en-1-yl)aniline with molecular iodine in methyl tert-butyl ether or acetonitrile was studied, as well as the interaction of this sulfonamide with N-bromosucinimide in dichloromethane. Synthesized (2R*,3R*)- and (2R*,3S*)-N-arylsulfonyl-2-(1-halogenoethyl)-3-methylindoline derivatives showed cytotoxic activity against HEK293 cells, SH-SY5Y, Jurkat, and HepG2 cell lines. The compounds (2R*,3S*)-N-arylsulfonyl-7-bromo-2-(1-halogenoethyl)-3-methylindoline cis- 4a , stereoisomeric (2R*,3R*)-trans- 4h and (2R*,3S*)-N-tosyl-7-chloro-2-(1-halogenoethyl)-3-methylindoline cis- 4h demonstrated selective toxicity against SH-SY5Y cell line (IC₅₀ ≈ 3 ÷ 5 μM), and did not affect HEK293, Jurkat, and HepG2 cells.     

Convenient synthesis and anticancer evaluation of novel pyrazolyl-thiophene,thieno[3,2-b]pyridine,pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine derivatives

The newly synthesized 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was utilized as a precursor for the synthesis of pyrazolyl-thiophene derivative, which undergoes cyclization upon treatment with benzaldehyde derivatives to provide pyrazolo[3,4-d]thieno[3,2-b]pyridines. Basic treatment of pyrazolyl-thiophene derivative with phenyl isothiocyanate followed by subsequent addition of chloroacetone and/or ethyl bromoacetate yielded the thiazolylidene-pyrazolyl thiophenes. In addition, the building block 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was converted into the corresponding thieno[3,2-b]pyridine compounds through its reactions with (DMF-DMA) and/or heating in sodium ethoxide. Moreover, the reaction of 7-hydroxy-5-oxo-N-phenyl-2-(phenylamino)-4,5-dihydrothieno[3,2-b]pyridine-3-carboxamide with 2-arylidenemalononitrile produced the new annulated pyrano[2,3-d]thieno[3,2-b]pyridines. The prepared thiophene-based compounds were evaluated against HepG2, PC3, and MCF-7 cancer cells, and normal fibroblast cell (WI38). The pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine compounds substituted with chlorophenyl group presented promising cytotoxic activities against HepG2 cancer cell line without any human toxicity. Docking study for the synthesized thiophene compounds delivered valuable insights about the binding interactions with the crystal structure of NS5B enzyme with PDB ID (4TLR).     

Synthesis,characterization, and biological activities of some novel thienylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines and related heterocycles

3-Cyano-5-ethoxycarbonyl-6-methyl-4-(2′-thienyl)-pyridine-2(1H)-thione ( 1 ) is synthesized and reacted with chloroacetamide or chloroacetonitrile to give 3-amino-5-ethoxycarbonyl-6-methyl-4(2′-thienyl)-thieno[2,3-b]pyridine-2-carboxamide 3a or its 2-carbonitrile analog 3b , respectively. Cyclocondensation of 3a with triethylorthoformate produced the corresponding pyridothienopyrimidineone 4 , which on heating with phosphorus oxychloride gave 4-chloropyrimidine derivative 5 . Compound 5 was used as key intermediate for synthesizing compounds 6 , 9 , 10 , 11 , and 12 upon treatment with some nucleophilic reagents such as thiourea, 5-phenyl-s-triazole-3(1H)-thione, piperidine, morpholine, or hydrazine hydrate, respectively. Reaction of pyridothienopyrimidinethione 6 with N-(4-tolyl)-2-chloroacetamide or ethyl bromoacetate afforded the corresponding S-substituted methylsulfanylpyrimidines 7 or 8 . The condensation of 3b with triethylorthoformate gave azomethine derivative 13 , which was reacted with hydrazine hydrate to give ethyl 3-amino-3,4-dihydro-4-imino-7-methyl-9-(2′-thienyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-8-carboxylate ( 14 ). Compounds 12 and 14 were used as precursors for synthesizing other new thienylpyridothienopyrimidines as well as isomeric thienyl-s-triazolopyridothieno- pyrimidines. All synthesized compounds were characterized by elemental and spectral analyses such as IR, ¹H NMR, and ¹³C NMR. In addition, majority of synthesized compounds were tested for their antifungal activity against five strains of fungi. Moreover, compounds 3a , 5 , 6 , 8 , and 22 were screened for their anticancer activity against HEPG-2 and MCF-7 cell lines.     

Synthesis of 1-(1,1-dimethylethyl)-1H-pyrazole-4-carboxylate ester derivatives

Attempts to prepare ethyl 5-cyano-1-(1,1-dimethylethyl)-1H-pyrazole-4-carboxylate ( 7 ) by the reaction of the corresponding 5-chloro derivative 1b with cyanide ion were unsuccessful. The chloro ester was synthesized from the corresponding amino ester la utilizing nonaqueous diazotization with nitrosyl chloride. An alternate process was developed which allowed the preparation of 7 from the corresponding 5-methyl ester 3 in four steps. The structure of the N-methylamide 8 synthesized from 7 was confirmed by X-ray diffraction analysis.     

Ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylates by a tandem addition‐elimination‐SNAr reaction

The ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate ring structure, important in several drug compounds, has been prepared in two steps from ethyl 2‐(2‐fluorobenzoyl)acetate. Treatment of this β‐ketoester with N,N‐dimethylformamide dimethyl acetal gives a 97% yield of the 2‐dimethylaminomethylene derivative. Reaction of this β‐enaminone with primary amines in N,N‐dimethylformamide at 140°C for 48 h then affords the 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate esters in 60–74% yields by a tandem addition‐elimination‐S_NAr reaction. The synthesis of the starting material as well as procedural details and a mechanistic scenario are presented. J. Heterocyclic Chem., (2011).     

Synthesis, Reactions, and Anti-arrhythmic activity of Substituted Heterocyclic Systems Using 5-Chloroanisic Acid as Starting Material

Summary. A series of substituted heterocyclic systems were prepared from N1-[4-(4-fluorocinnamoyl)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Treating of the cinnamoyl derivative with hydrazine hydrate in dioxane afforded a pyrazoline, which was reacted with morpholine and paraformaldehyde to give the N-substituted pyrazoline. Acylation of pyrazoline with acetyl chloride in dioxane afforded the N-acetyl analogue. Also, the cinamoyl derivative was reacted with methylhydrazine, phenylhydrazine, or ethyl cyanoacetate to yield the corresponding N-methyl-, N-phenylpyrazoline, pyrane, and pyridone derivatives. Condensation of the cinnamoyl derivative with cyanothioacetamide gave the pyridinethione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. Also, it was reacted with malononitrile or ethyl acetoacetae to give the cyano amino analougues and ethyl carboxylate, which was reacted with methylhydrazine to give the (indazolyl)phenyl derivative. On the other hand, reaction of cinnamoyl derivative with acetyl acetone afforded the cyclohexenyl derivative, which was reacted with hydrazine hydrate to give the [methylindazolyl]phenyl derivative. Condensation of the cinnamoyl derivative with guanidine hydrochloride or thiourea afforded the aminopyrimidine derivative and thioxopyrimidine. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Furopyridines. XVII . Cyanation,chlorination and nitration of furo[3,2-b]pyridine N-oxide

The N-oxide 2 of furo[3,2-b]pyridine ( 1 ) was cyanated by the Reissert-Henze reaction with potassium cyanide and benzoyl chloride to give 5-cyano derivative 3 , which was converted to the carboxamide 4 , carboxylic acid 5 , ethyl ester 6 and ethyl imidate 8 . Chlorination of 2 with phosphorus oxychloride yielded 2-9a , 3- 9b , 5- 9c and 7-chloro derivative 9d . Reaction of 9d with sodium methoxide, pyrrolidine, N,N-dimethylformamide and ethyl cyanoacetate afforded 7-methoxy- 10 , 7-(1-pyrrolidyl)- 11 and 7-dimethylaminofuro[3,2-b]pyridine ( 14 ) and 7-(1-cyano-1-ethoxy-carbonyl)methylene-4,7-dihydrofuro[3,2-b]pyridine ( 12 ). Nitration of 2 with a mixture of fuming nitric acid and sulfuric acid gave 2-nitrofuro[3,2-b]pyridine N-oxide ( 15 ).     

Ethyl 1,4‐Dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylates by a Tandem SNAr‐Addition‐Elimination Reaction

A series of N‐substituted 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylate esters has been prepared in two steps from ethyl 2‐(2‐chloronicotinoyl)acetate. Treatment of the β‐ketoester with N,N‐dimethylformamide dimethyl acetal in N,N‐dimethylformamide (DMF) gave a 95% yield of the 2‐dimethylaminomethylene derivative. Subsequent reaction of this β‐enaminone with primary amines in DMF at 120^oC for 24 h then afforded the target compounds in 47–82% yields by a tandem S_NAr‐addition‐elimination reaction. Synthetic and procedural details as well as a mechanistic rationale are presented.     

Irreversible enzyme inhibitors. XCI. candidate active-site directed irreversible inhibitors of thymidylate synthetase. II. 2-amino-6-methyl-5-(p-tolylsulfonamidopropyl)-4-pyrimidinols with N-substituents on the sulfonamide moiety

Three derivatives of 2-amino-6-methyl-5-(p-tolylsulfonamidopropyl)-4-pyrimidinol (I) with N - substituents on the sulfonamide group, namely bromoacetamidopropyl (XVI), m-bromoacetamidobenzyl (XXIVa), and p-bromoacetamidobenzyl (XXIVb), were synthesized as candidate active-site-directed irreversible inhibitors of thymidylate synthetase. The bromoacetamidopropyl derivative, (XVI), the p-bromoacetamidobenzyl derivative (XXIVb), and iodoacetamide showed irreversible inhibition of thymidylate synthetase, but XXIVa did not. Since iodoacetamide did inactivate the enzyme, but XXIVa did not, it cannot be ascertained whether XXIVb and XVI inactivate the enzyme by a random bimolecular mechanism or by the active-site-directed mechanism without evaluation of additional candidate inhibitors. Two synthetic routes were employed. The key intermediates for the bromoacetamidobenzyl sulfonamides (XXIV) were the corresponding nitrobenzyl sulfonamides (XXI); the latter were best prepared by reductive alkylation of 2-amino-5-aminopropyl-6-methyl-4-pyrimidinol (XXV) with a nitrobenzaldehyde followed by tosylation. The key intermediate for XVI was a toluenesulfonamide with a carbobenzoxyaminopropyl substituent on the nitrogen (XIV); the latter was synthesized via N-carbobenzoxy-N'-tosyl-1,3-diaminopropane (XI).     

Synthesis and antitumor activity of novel pyridino[2,3-d]pyrimidine urea derivatives

A series of novel N-(3-((6-bromopyrido[2,3-d]pyrimidin-4-yl)oxy)phenyl)pyrrolidine-1-carboxamide and 1-(3-((6-bromopyrido[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3-propylurea derivatives were synthesized. Their antitumor activities against human breast carcinoma cells (MCF-7) and human colon cancer cells (HCT-116) in vitro were evaluated, using sorafenib as a positive control drug. Anticancer bioassays indicated that several compounds exhibited appreciable anticancer activity against MCF-7 and HCT-116 cells. Particularly, compounds 9g and 8b demonstrated the most significant inhibitory effect against HCT-116 and MCF-7 cells, with inhibition ratios of 25.56% and 26.46%, respectively. Additionally, the synthesized pyridine[2,3-d]pyrimidine derivatives containing a urea group moieties exhibited antitumor activities against MCF-7 and HCT-116 cells in vitro.     

Spirans XXI. Synthesis of silaazaspiro[4.5]decanes and silaazaspiro[5.5]undecanes

N-(2-Dimethylaminopropyl)-8,8-dimethyl-8-sila-2-azaspiro[4.5]decane ( 1 ) and N-(3-dimethyl-aminopropyl)-9,9-dimethyl-9-sila-3-azaspiro[5.5]undecane ( 2 ) have been synthesized from 4,4-dimethyl-4-silacyclohexanone ( 5 ). Biological evaluation of 1 and 2 indicated cytotoxic action against human cancer cells grown in tissue culture.     

Antimicrobial Properties of Some New Synthesized Benzothiazole Linked Carboxamide,Acetohydrazide, and Sulfonamide Systems

We report herein the interaction of diethylethoxymethylene malonate ( 1 ) with 2‐cyanomethylbenzothiazole ( 7 ) to give diethyl 2‐(2‐benzothiazole‐2‐(3H)‐ylidiene)‐2‐(cyano ethyl) malonate ( 8a ) in excellent yield. Ethyl 4‐cyano‐1‐oxo‐1H‐benzo[4,5]thiazolo[3,2‐a]pyridine‐2‐carboxylate (9) was synthesized from 8a and subjected to react with hydrazine hydrate to give its corresponding acid hydrazide 10 . Condensation of 10 with different acid anhydrides afforded the corresponding benzothiazolo pyridine carboxamide derivatives 11 – 15 . In addition, we report a simple synthesis of N′‐(benzo[d]thiazol‐2‐yl)‐2‐((4‐ayl)amino)acetohydrazide derivative ( 17 ), which then reacted with different amines to give the corresponding acetohydrazide derivatives 19a – c . Moreover, compound 17 reacted with some sulfonamide derivatives to give the corresponding sulfonamide derivatives 20 and 22a , b .The newly synthesized compounds were established their structures on the bases of their correct analytical and spectral data and evaluated their antimicrobial activity. It was found that compounds 22a , b displayed the highest antimicrobial activity against the tested organisms.     

The synthesis of azole derivatives from 3-[(4-methylphenyl)amino]propanehydrazide and its N′-phenylcarbamoyl derivatives, and their antibacterial activity

Abstract  

5-[2-[(4-Methylphenyl)amino]ethyl]-1,3,4-oxadiazol-2(3H)-thione, 5-[2-[(4-methylphenyl)amino]ethyl]-1,3,4-oxadiazol-2(3H)-one, N-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[(4-methylphenyl)amino]propanamide, and a series of N-[(phenylcarbamoyl)amino]-3-[(4-methylphenyl)amino]propanamides and 3-[(4-methylphenyl)(phenylcarbamoyl)amino]-N-[(phenylcarbamoyl)amino]propanamides, and their thio analogues were synthesized from 3-[(4-methylphenyl)amino]propanehydrazide. 1,3,4-Oxadiazole-2(3H)-thione was converted to 4-amino-2,4-dihydro-5-[2-[(4-methylphenyl)amino]ethyl]-3H-1,2,4-triazole-3-thione, whereas cyclization of N′-phenylcarbamoyl derivatives provided thiazole, oxadiazoles, and thiadiazole, as well as triazole derivatives. Two of the synthesized compounds exhibited good antibacterial activity against Rhizobium radiobacter.     

Syntheses on the basis of diethyl (2-morpholinoethyl)malonate

New functionally substituted butan-4-olides were synthesized by reactions of diethyl (2-morpholinoethyl) malonate with 2-(allyloxymethyl)oxirane, 4-(oxiran-2-ylmethyl)morpholine, N-ethyl-N-(oxiran-2-ylmethyl)aniline, and 1-chloro-2,3-epoxypropane. 5-[2-(Morpholino)ethyl]barbituric and -thiobarbituric acids were also synthesized.     

Synthesis and Reactions of Some Substituted Heterocyclic Systems as Anti-arrhythmic Agents

Summary. A series of substituted heterocyclic systems were prepared from N ¹-[4-(2-thienylmethylene)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Condensation of the thienylmethylene derivative with guanidine hydrochloride, urea, or thiourea afforded the aminopyrimidine, pyrimidinone, and thioxopyrimidine derivatives. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. Treating of the thienylmethylene derivative with phenylhydrazine or hydrazine hydrate in dioxane afforded N-phenylpyrazoline and a pyrazoline, which was reacted with acetyl chloride in dioxane affording the N-acetyl analogue. The thienylmethylene derivative was reacted with malononitrile or ethyl cyanoacetate in the presence of ammonium acetate to yield the corresponding cyanoaminopyridine and cyanopyrimidone derivatives. Also, it was reacted with hydroxylamine hydrochloride in pyridine to give the oxime derivative, which was cyclized with acetic anhydride. On the other hand, condensation of the thienylmethylene derivative with ethyl cyanoacetate in the presence of sodium ethoxide or cyanothioacetamide gave the cyanopyrane and pyridine thione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Synthesis and Reactions of Some Substituted Heterocyclic Systems as Anti-arrhythmic Agents

A series of substituted heterocyclic systems were prepared from N ¹-[4-(2-thienylmethylene)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Condensation of the thienylmethylene derivative with guanidine hydrochloride, urea, or thiourea afforded the aminopyrimidine, pyrimidinone, and thioxopyrimidine derivatives. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. Treating of the thienylmethylene derivative with phenylhydrazine or hydrazine hydrate in dioxane afforded N-phenylpyrazoline and a pyrazoline, which was reacted with acetyl chloride in dioxane affording the N-acetyl analogue. The thienylmethylene derivative was reacted with malononitrile or ethyl cyanoacetate in the presence of ammonium acetate to yield the corresponding cyanoaminopyridine and cyanopyrimidone derivatives. Also, it was reacted with hydroxylamine hydrochloride in pyridine to give the oxime derivative, which was cyclized with acetic anhydride. On the other hand, condensation of the thienylmethylene derivative with ethyl cyanoacetate in the presence of sodium ethoxide or cyanothioacetamide gave the cyanopyrane and pyridine thione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole,pyrazole and/or pyridine ring systems

A series of novel nicotinonitrile derivatives were synthesized by hybridization with thiazole, pyrazole, and pyridine ring systems using 4-aminobenzohydrazide as link-bridge. The synthetic strategy of nicotinonitrile-thiazole analogues involves cyclization of the precursor N-phenyl thiosemicarbazide derivative 4 with chloroacetic acid and phenacyl bromide. The reaction of hydrazide 3 with acetylacetone and/or ethyl acetoacetate was applied as a synthetic route for accessing 2-((4-(pyrazole-1-carbonyl)phenyl)amino)-nicotinonitrile derivatives 9–10 . The 2-((4-(4-thiazolylidene-pyrazole-1-carbonyl)-phenyl)amino)nicotinonitriles 14–15 were obtained via a nucleophilic addition of pyrazolone 10 to phenyl isothiocyanate followed by cyclization with chloroacetone, phenacyl chloride, and/or ethyl bromoacetate. The 6-amino-4-aryl-3,5-dicyano-2-oxo-1-(4-substitutedbenzamido)-pyridines 19 were synthesized by Knoevenagel condensation N′-(2-cyanoacetyl)-benzohydrazide derivative 16 with substituted benzaldehydes followed by heating with malononitrile. All synthesized products were evaluated for their antioxidant potentialities using of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cation delcolorization assay. The nicotinonitrile-thiazole hybrid 6b was found the most promising antioxidant agent with inhibition activity 86.27%.     

Synthesis,cytotoxicity and apoptosis-inducing activity of novel 1H-benzo[d]imidazole derivatives of dehydroabietic acid

With the expectation of finding new and effective antitumor drugs, a series of novel N-(1H-benzo[d]imidazole-2-yl)-benzamide/benzenesulfonamide derivatives of dehydroabietic acid were synthesized and evaluated for cytotoxic activity against three human cancer cell lines (MCF-7, HeLa, and HepG2 cells) and one human normal hepatocyte cell line (LO2). As a result, a number of derivatives showed moderate to good antitumor activities. Among them, compound 8h exhibited the most potent activities against three cancer cell lines with IC₅₀ values of 0.87 ± 0.18, 9.39 ± 0.72, and 8.31 ± 0.64 μM, respectively, and was less active to normal hepatocyte LO2 cells. Further mechanism studies revealed that compound 8h could arrest the cell cycle of MCF-7 cells at S phase and induce the apoptosis of MCF-7 cells in ROS-mediated mitochondrial pathway.