Synthesis and antitumor activity of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones

The synthesis of 3-(5-imidazo]2,1-blthiazolylmethylene)-2-indolinones, analogs of compounds recently published, is described. The EIZ isomerism was studied by means of nuclear Overhauser effect experiments and X-ray crystallography. All the compounds were tested as potential antitumor agents. They were also tested as potential inhibitors of cyclin-dependent kinase 1 (CDK1), in order to determine if the antitumor activity was related to this mechanism of action. The results showed that under certain substitution conditions (5-methoxy group for the indole benzene ring and 2-methyl group for the imidazothiazole system), an interesting antitumor activity was found for some compounds. From the analysis of the antitumor data, 3-1(2,6-dimethylimidazo[2,1-bJ-thiazol-5-yl)methylenel-5-methoxy-2-indolinone was the most active of the whole series.     

Synthesis and antitumor evaluation of new polysubstituted thiazole and derived thiazolo[4, 5-d]pyrimidine systems

The synthesis of three categories of compounds containing the 1H-pyrazole ring linked to some dihydrothiazoles, thiazolidinones, and thiazolo[4, 5-d]pyrimidines through different linkages is described. Nine of the newly synthesized target compounds were selected by the NCI for in-vitro antitumor screening. Four compounds, namely 4a, 4b, 13, and 14, exhibited a broad spectrum of antitumor activity against most of the tested tumor cell lines. Compound 4a, 3-phenyl-4-amino-5-(3, 5-dimethyl-1-phenyl-1H-pyrazole-4-methylidenehydrazinocarbonyl)thiazole-2(3H)-thione proved to be the most active antitumor agent in the present study with GI(50), TGI, and LC(50) MG-MID values of 3.93, 41.7, and 91.2 microM, respectively. The same compound also exhibited high selectivity towards CNS SNB-75 and Ovarian IGROV1 cancer cell lines at both the GI(50) and TGI levels. Compound 4b, 3-(4-chlorophenyl)-4-amino-5-(3, 5-dimethyl-1-phenyl-1H-pyrazole-4-methylidenehydra-zinocarbonyl) thiazole-2(3H)-thione showed nearly the same pattern of activity as 4a but to a lesser extent. Compounds 13 and 14 displayed moderate antitumor activity against most of the tested tumor cell lines with GI(50) MG-MID values range of 20.4-80.6 microM and TGI MG-MID values of 55.5-95.5 microM.     

Synthesis, antitumor activity, and anti-HIV-1 testing of certain heterocyclic systems containing an adamantane nucleus

A new series of substituted 2-(1-adamantyl)-4H-3,1-benzoxazin-4-ones and 2-(1-adamantyl)-3-amino or alkyl-3,4-dihydroquinazolin-4-ones have been synthesized and tested for their antitumor and antiviral activities. Among the tested compounds, compounds 5a and 5b exhibited a broad spectrum antitumor activity with full panel (MG-MID) median growth inhibition (GI50) values of 3.2 and 4.9 microM respectively. Meanwhile, compounds 5c, 5d, 5h, 5i, and 5j showed moderate selectivity towards leukemia cell lines. On the other hand, compounds 4a and 4b possessed moderate Anti-HIV-1 potency with EC50 values of 50.3 and 69.2 microM respectively. Detailed synthesis, spectroscopic, and biological data are reported.     

Synthesis, characterization, and biological evaluation of certain 1,3-thiazolone derivatives bearing pyrazoline moiety as potential anti-breast cancer agents

A series of 5-arylidene-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-1,3-thiazol-4(5H)-ones were synthesized and screened for their in vitro antitumor activity against human breast adenocarcinoma cell line (MCF-7). Five of the test compounds exhibited good antitumor activity superior to the reference drug, doxorubicin, with IC₅₀ range 1.4–2.3 μM. Among the test compounds, 2-[3,5-bis(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-5-(2-methoxybenzylidene)-1,3-thiazol-4(5H)-one (3i) was found to show the most potent anticancer activity.     

Synthesis and antiviral activity of novel N-substituted derivatives of acyclovir

Novel N-substituted derivatives of acyclovir (1a) were synthesized and evaluated for their antiviral, antimetabolic, and antitumor cell properties in vitro. Monomethylation of 1a at positions 1, 7, and N-2 gave compounds 2-4, respectively. When positions 1 and N-2 were linked together by an isopropeno group, the tricyclic 9-[(2-hydroxyethoxy)methyl]-1,N-2-isopropenoguanine (5) was obtained. Compound 5 was then further methylated at positions N-2 and 7 to give 6 and 7, respectively. None of the new acyclovir derivatives showed any appreciable antimetabolic or antitumor cell activity. However, compounds 2 and 5 exhibited a marked antiherpetic activity. Their activity spectrum was similar to that of acyclovir, and their selectivity as inhibitors of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) was at least as great as, if not greater than, that of acyclovir.     

Synthesis of some new biologically active thiadiazolotriazinones--part III

4-Amino-6-arylmethyl/tert-butyl-3-mercapto-1,2,4-triazin-5(4H)-ones (1) were condensed with arylfuroic acids (2) to yield 7-(5-aryl-2-furyl)-3-arylmethyl/tert-butyl-4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones (3). The newly synthesized compounds exhibited antibacterial activity comparable to that of nitrofurazone. In addition, two compounds displayed in vitro antitumor activity with moderate growth inhibition against a panel of 60 tumor cell lines.     

Synthesis and structure-activity relationship studies of 2,3-dihydroimidazo[2,1-a]isoquinoline analogs as antitumor agents

5-Aryl-2,3-dihydroimidazo[2,1-a]isoquinolines were reported to have strong antitumor activity and one of the derivatives such as 5-[4′-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1-a] isoquinoline (1, SDZ 62–434) was found to be more effective than the clinical cytostatic agent edelfosine (2) inin vitro andin vivo assays. Currently SDZ 62–434 is in clinical trials in Europe. The structure-activity relationship studies of SDZ 62–434 showed that compounds with substitution on ring A were less active than the lead compound. Ring B in SDZ 62–434 was essential for the activity because compounds without B ring had no antitumor activity. Among the 3-arylisoquinolin-1-one derivatives, 3-[4′-(piperidonomethyl)phenyl] substituted analog had no antitumor activity but simple phenyl substituted compound, such as4, showed the most potent antitumor activity in various human tumor cell lines.     

Antitumor platinum(II) complexes with substituted 2-aminomethylpyridine ligands]

Reaction of K2PtCl4 with the substituted 2-aminomethylpyridines 9, 14, and 22 affords the corresponding dichloroplatinum(II) complexes 3-5. Compounds 3 and 22 show remarkable relative binding affinities for the estrogen receptor. Towards the hormone-independent P388-tumor of the CD2F1-mouse the platinum(II) complexes 4 and 5 are weakly active, complex 3 is inactive. Towards the hormone-independent MDA-MB 231-cell line, compounds 3-5, 9, 14, and 22 exhibit no significant antitumor activity. Towards the hormone-dependent MCF-7 cell line, compounds 3-5, 9, 14 show weak antitumor activity, whereas compound 22 exhibits strong inhibition.     

4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives as anti-tumor agents

A series of naturally occurring and synthetic novel oxapenam (4-oxa-1-azabicyclo[3.2.0] heptan-7-one) derivatives with their antitumor activity and the structure-activity relationship among this class of compounds is reported. Among the synthetic 4-oxa-1-azabicyclo[3.2.0]heptan-7-one having an ester, amide, ether derivatives of hydroxy group at C-3 position exhibited either no activity or reduced the antitumor activity in vitro. The 3-amino acid 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives showed better antitumor activity than naturally occurring 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivative G0069A. The trans isomers exhibited superior stability and activity over the cis isomers at the 3- and 5-position. Some of these compounds showed strong cytotoxicity against P388 and KB cells with IC(50) value ranging from 0.004 to 0.6 micro g/ml and they did not show any cross resistance against ADR, 5-FU and VCR resistant cell lines in vitro. Of these, 3-hydroxy methyl, 3-(2-amino-2-carboxy-1-benzyloxy ethyl) and 3-(2-amino-2-carboxy ethyl) 4-oxa-1-azabicyclo[3.2.0] heptan-7-one inhibited 71-84% in vivo tumor growth of colon 26 and S-180 cells subcutaneously implanted into mice at a varying dose between 0.625-15 mg/kg/day depending upon the compounds and the tumor cell lines.     

Synthesis and anticancer activity of isatin-based pyrazolines and thiazolidines conjugates

The synthesis and antitumor activity screening of novel isatin based conjugates with thiazolidine and pyrazoline moieties were performed. Reaction of 3,5-diaryl-4,5-dihydropyrazoles with chloroacetyl chloride yielded starting 2-chloro-1-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-ethanones which were utilized in alkylation of isatin and 5-bromoisatin. Thus, corresponding 1-[2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-2-oxoethyl]-1H-indole-2,3-diones (1a-1d) have been obtained. The compounds 1a-1d have been used in Knoevenagel condensation with 4-thiazolidinones for obtaining a series of 5-ylidenederivatives 2a-2f and 3a-3d. The synthesized compounds were tested for their anticancer activity in NCI60 cell lines. Among the tested compounds, 5-bromo-1-{2-[5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl]-2-oxoethyl}-1H-indole-2,3-dione (1d) was found to be the most active candidate with selective influence on leukemia subpanel tumor cell lines with GI(50) values range of 0.69-3.35 μM.     

Synthesis and antitumor activity of halogen-substituted 4-(3,3-dimethyl-1-triazeno)quinolines

Halogenated 4-(3,3-dimethyl-1-triazeno)quinolines were synthesized as potential antitumor agents on the basis of the biochemical pharmacological properties of existing triazenes, their structural-activity relationships, and the high melanin binding of chloroquine and iodoquine in vivo and in vitro. They were synthesized by diazotization of appropriate halogen-substituted 4-aminoquinolines in fluoboric acid at -5 degrees C followed by coupling with dimethylamine. Among these new compounds, 8-chloro-4-(3,3-dimethyl-1-triazeno)quinoline produces significant antitumor activity against both P-388 and L1210 murine leukemias. Although only marginally active or inactive against P-388, the other chloro, bromo, or iodo analogues show activity against L1210 comparable to that of dacarbazine (DIC). However, none of these compounds is active against B-16 melanoma. Compared with DIC these new agents demonstrate a higher in vitro affinity for melanin; however, this affinity is apparently not correlated with their antitumor activity.     

1-(5-取代糠基)吲哚啉-2-酮衍生物的合成和初步抗肿瘤活性

为了寻找具有较好抗肿瘤活性的新型吲哚啉-2-酮类化合物，本研究以5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯与5位不同取代的吲哚啉-2-酮(2a～2d)为原料，首先经缩合得3-吡咯亚甲基-吲哚啉-2-酮(3a～3d)，再经N烃化反应得到1-(5-甲酰基糠基)-3-(吡咯亚甲基)-吲哚啉-2-酮(4a～4d)，然后与吲哚啉-2-酮缩合得到以5-亚甲基糠基连接的双吲哚啉-2-酮化合物(5a～5d)。所合成的12个新型吲哚啉-2-酮类化合物的结构经核磁共振谱、质谱和元素分析确认。采用四氮唑盐(MTT)还原法测试所合成化合物的体外抗肿瘤活性，结果表明所合成的化合物均有一定的抗肿瘤作用，其中6个化合物对SPC-A1肺癌肿瘤株体外抑制活性优于舒尼替尼，特别是化合物5a～5d， IC₅₀值均小于5 μmol·L^-1，值得作为抗肿瘤药物先导化合物。     

Potential antitumor agents. 49. 5-substituted derivatives of N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide with in vivo solid-tumor activity

Derivatives of N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide bearing a wide variety of different groups at the 5-position (and for comparative purposes at the 7-position) have been prepared, and their physicochemical properties and biological activities have been determined. Although both 5- and 7-substituted compounds bind equally well to DNA by intercalation, only the 5-substituted compounds have in vivo antitumor activity. All the 5-substituted compounds showed in vivo antileukemic activity, but only those bearing electron-withdrawing substituents sufficiently powerful to ensure the acridine chromophore was uncharged at physiological pH showed activity in vivo against the Lewis lung solid tumor. The weakly basic derivatives do not show greater intrinsic cytotoxicity or selectivity toward solid tumor cells, and their broader spectrum of in vivo antitumor activity is attributed to the fact that they exist predominantly as monocations, which can distribute more efficiently.     

Adenosine deaminase inhibitors. Synthesis and biological activity of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine

Two new deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1), 7-deaza-EHNA (6) and 1,3-dideaza-EHNA (11), were synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity and compared with EHNA, 1-deaza-EHNA (2), and 3-deaza-EHNA (3). Substitution of a methine group for a nitrogen atom in the 7-position of the purine moiety of EHNA produces a dramatic drop in the inhibitory activity (Ki = 4 X 10(-4) M) whereas compounds 2 and 3 are still good inhibitors (Ki = 1.2 X 10(-7) M and 6.3 X 10(-9) M respectively). EHNA and its deaza analogues so far synthesized were also tested in vitro for their antiviral and antitumor activity in a range of cellular systems. EHNA and 1-deaza-EHNA are equiactive as inhibitors of human respiratory syncytial virus (HRSV) replication (MIC = 6.25 micrograms/mL) while the other compounds are inactive. On the other hand, all the examined compounds displayed an antitumor activity comparable to that of the reference compound 1-beta-D-arabinofuranosyladenine (ara-A), 7-deaza-EHNA being the most active of all. The results obtained showed that there is no correlation between adenosine deaminase inhibition and antiviral or antitumor activity in this series of compounds. 3-Deaza-EHNA, the most active inhibitor of ADA among the EHNA deaza analogues, greatly potentiates the antitumor activity of ara-A in vitro. In vivo activity was observed only when the two compounds were used in combination.     

Synthesis and antitumor screening of new 1,7-diphenyl-3-(1,3-disubstituted-1H-pyrazole-4-carbonyl)-[1,2,4]triazolo[4,3-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-5(1H)-ones

A new series of 3-(1,3-disubstituted-1H-pyrazole-4-carbonyl)-1,7-diphenyl-[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones 4 was prepared by reaction of the enaminone 2 with hydrazonoyl halides 3. The preliminary screening for antitumor activity of the synthesized compounds was carried out against Ehrlich Ascites Carcinoma tumor cells. The results revealed that the studied compounds 4 have low or no antitumor activity towards EAC tumor cells.     

Synthesis and biological evaluation of new thiazolopyrimidines

In this study, a series of 4-amino-5-cyano-3-substituted-2,3-dihydrothiazol-2-thiones (1a-c), as well as their triazolo and triazinopyrimidine derivatives such as 8-substituted-3-benzyl-5-methylthiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2-thiones (4-6, 10) and 3-benzyl-5-methyl thiazolo[5,4-e]pyrimidino[3,4-b][1,2,4]triazin-2-thiones (7a-b) were prepared as potential antimicrobial and antitumor agents. Some of the tested compounds showed promising antimicrobial activity and non of them showed any appreciable antitumor activity.     

New alpha-amino phosphonic acid derivatives of vinblastine: chemistry and antitumor activity

A series of new amino phosphonic acid derivatives of vinblastine (1, VLB) has been synthesized and tested in vitro and in vivo for antitumor activity. The compounds were obtained from O4-deacetyl-VLB azide. All of the new products studied were capable of inhibiting tubulin polymerization in vitro. The most potent antitumor compounds bore an alkyl substituent on the phosphonate. In these compounds, the anti-tumor activity strongly depended on the stereochemistry of the phosphonate. The phosphonate (1S)-[1-[( O4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastin-3-yl] carbonyl]amino]-2-methylpropyl]phosphonic acid diethyl ester exhibited a remarkable activity against cancer cell lines both in vitro and in vivo.     

一组新的N-羟基肉桂酰胺类组蛋白去乙酰化酶抑制剂的合成和初步活性研究

目的设计合成了一组新的N-羟基肉桂酰胺类衍生物并测定其对组蛋白去乙酰化酶（HDACs）的抑制活性。方法以阿魏酸为原料，经酯化、Williamson反应、皂化、缩合4步反应合成了一组新的N-羟基肉桂酰胺类衍生物；用组蛋白去乙酰化酶活性检测试剂盒测定该组化合物体外抑酶活性。结果与结论合成了11个未见文献报道的N一羟基肉桂酰胺类衍生物，其结构经过。H-NMR、MS、和IR确认。其中化合物5a、5b、5e和5k的体外抑酶活性较强（IC50=2--15 μmol·L^-1），有可能具有抗肿瘤活性，值得进一步研究。     

Synthesis and biological evaluation of some quinazoline derivatives as antitumor and antiviral agents

A new series of 4-(4-aryl-1-piperazinyl)quinazolines 4a-f, 4-(3-substituted phenylamino)quinazoline derivatives 5a-h, 2-methoxycarbonylphenylaminoquinazoline derivatives 6a, b, 2-hydrazinocarbonylphenylaminoquinazolines 7a, b and 2-aryl-1-(substituted 4-quinazolinyl)-1,4-dihydro-5-oxo-5H-1,3,4-benzotriazepines 8a-j have been synthesized and tested for their antitumor and antiviral activities. Among them, compounds 5a-d exhibited broad spectrum antitumor activity with full panel median growth inhibition (GI50) at concentrations of 3.2, 2.0, 4.8, 4.0 mumol/l and total growth inhibition at concentrations of 56.5, 51.0, 63.0 and 73.0 mumol/l, respectively. Compounds 7a and 7b showed moderate selectivity toward leukemia cell line. On the other hand, compounds 8a and 8b showed moderate anti HIV-1 potency with EC50 values of 40.5 and 52.8 mumol/l, respectively. The detailed synthesis, spectroscopic and biological data are reported.     

(1-Pyrenylmethyl)amino alcohols, a new class of antitumor DNA intercalators. Discovery and initial amine side chain structure-activity studies

In the series of 1-pyrenylmethylamines studied in this work the relationships among structure, interaction with DNA, and murine antitumor activity were examined. Binding studies show that all of these 1-pyrenylmethylamine derivatives bind to some extent to DNA by intercalation. The presence of additional basic amine groups in the side chain enhances DNA binding due to electrostatic interactions. Those compounds containing only a single basic benzylic amine bind similarly to DNA. Only the presence of bulky side chains appears to decrease the DNA interactions in the compounds examined. Although antitumor activity is seen for (1-pyrenylmethyl)amino alcohols, useful antitumor activity in the series is limited to those congeners bearing the 2-amino-1,3-propanediol-type side chain. These derivatives bind moderately to DNA. DNA binding is a necessary but not sufficient criterion for antitumor activity in the series. In addition, the strength of DNA binding does not correlate with the antitumor activity in the group of active compounds. Three related 2-[(arylmethyl)amino]-1,3-propanediol derivatives (AMAPs) [crisnatol (770U82), 773U82, and 502U83] are currently in clinical trials as potential antitumor agents.