Synthesis and Antitumor Activity of New Derivatives of Podophyllotoxin

A series of analogues of etoposide (VP-16), the C-4 alkylamino-substituted 4'demethyl-epipodophyllotoxins, have been synthesized and studied for their activity to inhibit L1210 and KB cells in vitro. Most new compounds are as active or more active than VP-16 in their inhibition of both L1210 and KB cells.

Synthesis and Antitumor Activity of Podophyllotoxin Analogues

Seven podophyllotoxin analogues were synthesized by condensation of 4′ demethyl epipodophyllotoxin 10 with 5 alkyl 4 amino 3 mercapto 1,2,4 triazoles 9(a g) in the presence of TFA(CF 3COOH). Their antitumor activities were screened in vitro against HL 60 and K 562 cells.

Synthesis and Antitumor Activity of4β-(1,2,3-Triazol-1-yl) podophyllotoxins

Three 4β-(1,2,3-triazol-1-yl) podophyllotoxins 2～4 have been synthesized and testedtar their antitumor activity in vitro. The compound 3 was found to be much more cytotoxic than theclinically used etoposide (VP-16) against L 1210 cells.

THEORETICAL STUDY OF PODOPHYLLOTOXIN AND QUINOLONE ANALOGUES AS ANTITUMOR DRUGS

Objective: To study the active sites of podophyllotoxin derivatives. Methods: Some podophyllotoxin derivatives were analyzed by quantum and mechanics method. Results: Some information was given according to the calculation results about HOMO and LUMO electron density. The C-4 position is the position for effective modification. The B ring and E ring are important active centers. Conclusion: The hole of positive charge in B ring easily combines with an acceptor within the molecular. Some quinolones with similar electronic construction to podophyllotoxin may have antitumor activity.

Synthesis and Antitumor Activity of 3-[2-(4-Hydroxy-Phenyl)-Ethyl]-Benzo[d] Isoxazole-4,6-Diol

A new phloretin derivative 1 3-[2-(4-hydroxy-phenyl)-ethyl]-benzo[d] isoxazole-4,6-diol (yield 63%) was synthesized from phloretin by carbonyl nucleophilic addition condensation reaction. Its structure was characterized by 1H NMR, 13C NMR and HR-MS. The phloretin, compound 1, resveratrol and acetylated resveratrol were determined by comparing them with paclitaxel. Anti-tumor activity of alcohol on SPC-A1, EC109, A549, MCF-7 and MDA-MB-231 cell lines. Compound 1 showed better antitumor activity than docetaxel against A549 tumor cells.

Synthesis and Anticancer Activity of 4b-Triazolepodophyllotoxin Glycosides

A series of novel 4b-triazole-podophyllotoxin glycosides were synthesized by utilizing the Click reaction.Evaluation of cytotoxicity against a panel of five human cancer cell lines(HL-60,SMMC-7721,A-549,MCF-7,SW480)using MTT assay shows that most of these compounds show weak cytotoxicity.It was observed that compound 16 shows the highest activity with IC50 values ranging from 2.85 to 7.28 lM,which is more potent than the control drugs etoposide and cisplatin against four of five cancer cell lines tested.Compound 16 is characterized with an a-D-galactosyl residue directly linked to the triazole ring and a 40-OH group on the E ring of the podophyllotoxin scaffold.HPLC investigation of representative compound indicates that incorporation of a sugar moiety seems to improve the chemical stability of the podophyllotoxin scaffold.

Synthesis and cytotoxicity of novel podophyllotoxin derivatives

In order to find novel synthetic antitumor agents with superior cytotoxicity and overcoming multidrug resistance, a novel series of 4β-N-substituted podophyllotoxin derivatives were synthesized and evaluated as potential antitumor agents. Seven novel podophyllotoxin derivatives were synthesized by linking 4β-amino-4-deoxypodophyllotoxin with N-substituted 5-methylindol-3- yl-glyoxyl chlorides and tested against K562 and K562/A02 using SRB methods in vitro, KB and KBVusing MTT methods in vitro.

Design,Synthesis and Crystal Structure of the Antitumor Agent N1-(2-(4-Methoxy-2-nitrophenoxy)-2-dimethyl acyloxymethyl)-5-fluorouracil

A series of novel 5-fluorouracil derivatives were designed and synthesized, and the compound N1-（2-（4-Methoxy-2-nitrophenoxy）-2-dimethyl acyloxymethyl）-5-fluorouracil（C（16）H（16）FN3O8, Mr = 397.32） was structurally characterized by 1H-NMR, 13C-NMR, ESI-MS and single-crystal X-ray diffraction. The compound crystallizes in triclinic, space group P1 with a = 5.6725（7）, b = 8.7443（19）, c = 18.116（3） ？, α = 98.226（17）, β = 96.247（12）, γ = 94.318（14）°, V = 880.3（3） ？~3, Z = 2, T = 294.12（10） K, μ（Mo Kα） = 0.128 mm^（-1）, Dc = 1.499 g/cm3, F（000） = 412 and GOOF = 1.105. 5175 reflections were measured（6.868≤2θ≤52.042°）, and 3416 were unique（Rint = 0.0272, Rsigma = 0.0579） and used in all calculations. The final R = 0.0551（I 〉 2σ（I）） and w R = 0.1288（all data）. The structure of the crystal was stabilized by hydrogen bonds and the antitumor activity of the compound was analyzed by MTT assay.

Synthesis,Crystal Structure and Antitumor Activity of a New Zn(Ⅱ) Complex Based on N-Acetyl-L-phenylalanine and 1,10-Phenanthroline

A new Zn（Ⅱ） complex, [Zn（L）2（phen）（H2O）]（1, HL = N-acetyl-L-phenylalanine, phen = 1,10-phenanthroline） has been synthesized and characterized by elemental analysis, IR and X-ray single-crystal diffraction analysis. The Zn（Ⅱ） complex belongs to monoclinic, space group P21 with a = 12.6749（13）, b = 5.5965（6）, c = 22.985（2） A, β = 104.296（2）°, V = 1580.0（3） A^3, Z = 2, Mr = 676.02, Dc = 1.421 μg·m^（-3）, μ = 0.833 mm^-1, F（000） = 704, and the final R = 0.0460, wR = 0.0899 for 4422 observed reflections with I 〉 2σ（I）. The molecules form a 1D chained structure by hydrogen bonds. The antitumor activities of Zn（Ⅱ） complex against human hepatoma SMMC-7721 cells, human lung adenocarcinoma A549 cells and human colon carcinoma WiDr cells have also been investigated.

Synthesis, Crystal Structure and Antitumor Activity of 4-(tert-butyl)-5-(1H-1,2,4-triazol-1-yl)-N-(2-hydroxy-3,5-diiodinebenzyl)-thiazol-2-amine

The title compound, 4-（tert-butyl）-5-（1 H- 1,2,4-triazol- 1 -yl）-N-（2-hydroxy-3,5-diio- dinebenzyl）thiazol-2-amine, was synthesized via the reduction of 4-（tert-butyl）-5-（1H-l,2,4- triazol-l-yl）-N-benzylidene-thiazol-2-amine with NaBH4, and its crystal structure was determined by single-crystal X-ray diffraction. The compound crystallizes in monoclinic system, space group P21/c with a = 7.91944（19）, b = 10.5250（3）, c = 24.4985（6） A, Z = 4, V = 2041.66（9） A3, Mr = 599.22, Dc = 1,949 Mg/m3, S = 1.120, p = 3.203 mm-1, F（000） = 1152, the final R = 0.0283 and wR = 0.0592 for 3490 observed reflections （I 〉 2σ（I））. X-ray analysis displays that the crystal water takes part in three intermolecular hydrogen bonds of O（2）-H（2A）…O（1）, O（2）-H（2B）…N（I） and N（5）-H（5）…O（2）, and an octatomic ring R^（8） is formed via intramolecular hydrogen bond of O（I）-H（IA）…N（4）. Furthermore, the I…I contacts are involved in stabilizing the overall three-dimensional network structure. The preliminary biological test shows the title compound has good antitumor activity with the IC50 value of 26 μM against the Hela cell line.

The Synthesis of Podophyllotoxin Derivatives with Macrocyclic Dilactone

Starting from podophyllotoxin, five new derivatives with macrocyclic dilactone 5 similar to 9 have been synthesized,and their structures were confirmed by IR, MS,H-1 NMR as well as HRMS. The key step is cyclization by high dilution method.

Microwave Solvothermal Synthesis, Crystal Structures and in Vitro Antitumor Activities of Di-n-butyltin Piperonylate with a Sn4O4 Ladder Framework

A two-dimensional supramolecular compound di-n-butyltin piperonylate, {（μ3-O）（μ2-OMe）（n-Bu2Sn）2[O2CAr（C2H4O）]}2 constructed by hydrogen bonds with a Sn4O4 ladder-like framework, was obtained by the microwave-assisted solvothermal reaction of di-n-butyltin oxide precursor with the piperonylic acid in methanol environments. The composite was characterized by elemental analysis and IR（~1H, ^（13）C and ^（119）Sn） NMR spectra. The compound crystallizes in monoclinic system, space group P21/n with a = 13.3690（12）, b = 14.1442（14）, c = 16.4022（16） A, β = 107.191（6）°, V = 2963.0（5） A^3, Z = 2, Dc = 1.520 g/cm^3, F（000） = 1368, μ = 1.719 mm^（-1）, Mo Kα radiation（λ = 0.71073 A）, the final R = 0.0495 and w R = 0.1260 for 6780 observed reflections with I 〉 2σ（I）. Its X-ray crystallography diffraction analyses show a Sn4O4 ladder-like skeleton, in which two endocyclic tin and one exo tin atoms are bonded to the μ3-O atom. In addition, one endocyclic tin and one exo tin atoms are respectively bonded to the μ2-O atom from methanol. The ladder-like molecule has a three-ring fused skeleton, which is almost coplanar. The endocyclic and exocyclic tin atoms were all five-coordinated with distorted trigonal bipyramidal geometry. The antitumor activity showed that the compound had higher activities than cisplatin in HT-29, HepG2, MCF-7, KB and A549 cell line in vitro.

Synthesis,Crystal Structure and Antitumor Activity of 6-Chloro-1-((6-chloropyridin-3-yl)methyl)-3-phenyl-1H-benzofuro[3,2-c]pyrazole

The title compound 6-chloro-l-（（6-chloropyridin-3-yl）methyl）-3-phenyl-lH-benzofuro[3,2-c]pyrazole（5,C21H13Cl2N3O,Mr = 394.26） was synthesized and characterized by elemental analysis,^1H NMR,^13C NMR and X-ray single-crystal diffraction.The structure reveals that the crystal belongs to the triclinic system,space group P1 with a = 7.8829（8）,b = 10.3281（10）,c = 11.7615（12）A°,α = 83.5552（2）,β = 79.921（2）,γ = 70.189（2）°,V= 885.54（15） A°3,Z = 2,Dc =1.479 g/cm^3,μ = 0.383 mm^-1,F（000） = 404,R = 0.0538 and wR = 0.1335 for 2453 observed reflections with I 〉 2σ（I）.The result reveals that the crystal structure of the title compound 5 is stabilized by three C-Cl…π interactions and π…π stacking interaction.In addition,the preliminary investigation showed that 5 exhibits remarkably good antitumor activity against the MCF-7 and A549 cell lines.

SYNTHESIS AND ANTITUMOR ACTIVITY OF PEPTIDYL-N^2-HYDROXYMETHYL-5-FLUOROURACIL

Six hydrophobic peptidyl and four amino acid (L-Val, L-Leu, L-Phe, L-Gly) derivatives of 5-fluorouracil(5-FU) were synthesized. The structure of these compounds were characterized by ~1H-NMR, IR, UV spectra and elemental analysis. The antitumor activity was test- ed against EAC cells in vitro.

STUDIES ON THE SYNTHESIS AND ANTITUMOR ACTIVITY OF AMINO ACID ESTER DERIVATIVES OF BENZISOSELENAZOLONE

This paper reports a simple method for the synthesis of amino acid ester derivatives of benzisoselenazolone.Their anticancer activity is also given.

Synthesis,Crystal Structure and Antitumor Activities of Ethyl(R)-2-(Biphenyl-4-carbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate

The title compound,ethyl（R）-2-（biphenyl-4-carbonyl）-2,3,4,9-tetrahydro-1H-pyri do-[3,4-b]indole-1-carboxylate（C（27）H（24）N2O3） has been synthesized,and its structure was charac-terized by ^1H-NMR,^13C-NMR,ESI-MS and single-crystal X-ray diffraction.It crystallizes in the orthorhombic system,space group Pbca with a = 16.9950（8）,b = 9.5445（4）,c = 28.3188（3）A,V = 4593.6（3）A^3,Z = 8,T = 294.64（10） K,μ（MoKα） = 0.08 mm^-1,Dc = 1.228 g/cm^3,F（000） = 1792 and GOOF = 1.036.11836 reflections were measured（7.04≤2θ≤52.04°）,and 4506 were unique（R（int）= 0.0393,R（sigma ）= 0.0546） and used in all calculations.The final R = 0.0576（I 〉 2σ（I）） and wR = 0.1563（all data）.The preliminary biological tests show that the title compound has a good antitumor activity against Hela in vitro with the IC（50） value of 4.71 μmol/L.

Synthesis, Crystal Structure and Antitumor Activity of (E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5- yl)-3-(2-methoxyphenyl)-2-(1H-1,2,4-triazol-1-yl)propenol

The title compound, （E）-1-（7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl）- 3-（2-methoxyphenyl）-2-（1H-1,2,4-triazol-1-yl）propenol （3a）, was synthesized by the Aldol con- densation reaction of 1-（7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl）-2-（1,2,4-triazol- 1-yl）ethanone with 2-methoxybenzaldehyde and then reduced with NaBH4, and its crystal structure was determined by single-crystal X-ray diffraction： monoclinic system, space group P21 with a = 6.2002（3）, b = 12.8452（7）, c = 13.2257（7） ？, Z = 2, V = 1031.23（9） ？3, Mr = 407.46, Dc = 1.312 Mg/m3, S = 1.054, μ = 0.091 mm-1, F（000） = 432, the final R = 0.0353 and wR = 0.0769 for 3161 observed reflections （I 〉 2σ（I））. X-ray analysis displays that the title compound adopts an E configuration for the C（7）=C（8） double bond and S configuration for the chirality center with the specific rotation of –63.75°. Furthermore, the stability of the crystal was maintained through the intermolecular hydrogen bond O（1）–H？？？N（3）. The antitumor assay exhibits that the title compound 3a （E configuration） has a good antitumor activity against the Hela cell line with the IC50 value of 36.9 μM, which is better than that of 3b （Z configuration）.

Synthesis and antitumor activity of N^1-acetylamino-(5-alkyl/aryl-1,3,4-thiadiazole-2-yl)-5-fluorouracil derivatives

A new series of N^1-acetylamino-（5-alkyl/aryl- 1,3,4-thiadiazole-2-yl）-5-fluorouracil derivatives were designed and synthesized. These compounds have not been reported in literature, and their structure chemical were confirmed by IR, ^1H NMR and MS （HRMS）. The results of antitumor inhibitory activity test showed that some compounds possess more potent antitumor inhibitory activity than 5-fluorouracil.

Synthesis,Crystal Structure and Antitumor Activities of(14S)-2,14-diphenyl-6,6a,11,12-tetrahydro-5H,10H,14H-[1,8]naphthyridino[1,2-c]pyrido[3,2,1-ij]quinazoline-3-carbonitrile

The title compound（14 S）-2,14-diphenyl-6,6 a,11,12-tetrahydro-5 H,10 H,14 H-[1,8] naphthyridino[1,2-c]pyrido[3,2,1-ij]quinazoline-3-carbonitrile（C31 H26 N4, Mr = 454.56） has been synthesized with 2-aminonicotinaldehyde and 3-oxo-3-phenylpropanenitrile as starting materials, and its crystal structure was determined by single-crystal X-ray diffraction for the first time. The crystal belongs to the triclinic system, space group P1 with a = 8.5833（8）, b = 11.9168（12）, c = 14.4424（14） ？, α = 84.208（3）o, β = 88.427（3）o, γ = 73.704（3）o, V = 1410.7（2） ？3, Z = 2, F（000） = 480, μ = 0.064 mm–1, S = 0.966, the final R = 0.0484 and wR = 0.1388 for 5041 observed reflections with I 〉 2s（I） and 316 variable parameters. The preliminary biological tests show that the title compound has a good antitumor activity against K562 in vitro.

Synthesis and antitumor activity of novel 10-amino acids ester homocamptothecin analogues

Nine racemic homocamptothecin derivatives were synthesized and in vitro antitumor activities were evaluated by standard MTT method. The results showed that some of the compound had higher antitumor activity than iritecan.