Synthesis and anticancer effects of pongamol derivatives on mitogen signaling and cell cycle kinases

Abstract  

A series of oxazole and pyrazole derivatives of pongamol (1) were designed and synthesized to examine their anti-cancer activity. The cytotoxicity of these compounds was examined in three different human tumor cell lines, IMR-32, HeLa and Jurkat. Although all compounds tested were quite effective than the pongamol against all the three different types of cancer cell lines examined, the compounds (2), (5), and (6) were found to be the most active compounds of this series.     

Synthesis and biological evaluations of enoxacin carboxamide derivatives

The present work deals with the synthesis of various enoxacin analogues via nucleophilic substitution of 3-carboxylic acid moiety of the drug by aromatic amines. The free carboxylic group was utilized in the formation of amides and the effect of functional group exchange on different biological activities of the parent was evaluated. The structure of these derivatives was established by various spectroscopic techniques and mass spectrometry. The derivatives were evaluated as antibacterial agents against a series of Gram-positive and Gram-negative bacteria whereby some of them displayed considerably improved antimicrobial profile against Gram-negative test strains. Additionally unlike enoxacin, the derivatives were also found to modulate oxidative burst response of phagocytes exhibiting moderate to significant inhibitory activity.     

Synthesis and cytotoxicity of furfural derivatives

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 26, No. 1, pp. 45–48, January, 1992.     

Synthesis and cytotoxicity of kaempferol derivatives

In the present study, we developed a simple approach for the structural modifications of kaempferol (1). A new compound, 3,5-dihydroxy-2-(4-hydroxyphenyl)-6,8,8-tris(3-methylbut-2-en-1-yl)-4H-chromene-4,7(8H)-dione (5) together with three known compounds, 8-prenylkaempferol (2), 6-prenylkaempferol (3) and 6,8-diprenylkaempferol (4), were synthesized under different reaction conditions. All of derivatives were synthesized in a structural modification way for the first time. Their structures were primarily elucidated by NMR and MS analyses. Compounds 2, 3 and 5 exhibited prominent cytotoxic activity against MDA-231 (IC₅₀ values were 9.45±0.20μM, 7.15±0.37 μM and 6.92±0.30 μM, respectively) and MCF-7 (IC₅₀ values were 10.08±0.57μM, 10.04±0.23 μM and 2.15±0.20 μM,respectively) breast cancer cells.     

Novel pyrazolopyrimidine urea derivatives: Synthesis,antiproliferative activity,VEGFR-2 inhibition,and effects on the cell cycle profile

A series of novel diaryl urea pyrazolopyrimidine derivatives was designed and synthesized. All the synthesized compounds were evaluated for cytotoxic activity by the National Cancer Institute. A significant antiproliferative activity at a 10-µM dose was shown by four compounds ( 5c, 5e, 5g , and 5h ), and they were accordingly evaluated at five concentrations. They showed a potent and broad-spectrum antiproliferative activity, with GI₅₀ values between 0.553 and 3.80 µM and TGI values in the range of 2.17–100 µM. These four compounds potently inhibited the vascular endothelial growth factor receptor-2 (VEGFR-2) with IC₅₀ values in the nanomolar range. Molecular docking attributed their potent VEGFR-2 inhibitory activity to their interactions with key amino acids in the VEGFR-2 active site. Their flow cytometric analysis showed that they exerted their cytotoxic activity by reduction of the cellular proliferation and by induction of cell cycle arrest at the G2/M phase. Additionally, they induced DNA degradation or fragmentation, confirming the role of apoptosis in the cancer cell death and cytotoxicity induced by these compounds.     

人参二醇衍生物的合成及其细胞毒活性研究

目的 为了获得细胞毒活性更强人参二醇衍生物 方法 利用生物电子等排原理制备3位胺基-人参二醇,再合成人参二醇3位胺基的肉桂酸类、NO供体类衍生物以及其它类型的人参二醇衍生物18个,其中有12个化合物未见文献报道,其结构均经过₁^H NMR, _¹3^C NMR核磁共振、质谱确证。这些化合物中的16个化合物用MTS法对人白血病细胞株HL-60、肝癌细胞株SMMC-7721、肺癌细胞株A-549、乳腺癌细胞株MCF-7、结肠癌细胞株SW480等肿瘤细胞株进行了细胞毒活性评价。结果 药理活性评价结果显示,化合物6c、7以及7j对五株肿瘤细胞均有较强的抑制活性,特别是化合物7对HL-6与SMMC-7721细胞抑制的IC₅₀分别为3.41,4.51 μM,显著优于人参二醇的细胞毒活性。结论 7和7j可以作为先导化合物进行更深入的研究。     

Synthesis and cytotoxicity of novel chrysin derivatives

A series of chrysin derivatives 8a–8v were prepared and tested in vitro against HCT-116 (human colon cancer cell line), Hela (human cervical carcinoma cell line), DU-145 (human prostate cell line), K562 (human leukemia cell line), and SGC-7901 (human gastric cancer cell line). The chemical structures of these compounds were confirmed by means of MS, IR, ¹H NMR, ¹³C NMR, and elemental analysis. Among these derivatives, 7-(2-(piperazin-1-yl)ethoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one, 8n, had the strongest activity against HCT-116, Hela, DU-145, K562, and SGC-7901 cells. .     

Synthesis and cytotoxicity evaluation of novel podophyllotoxin derivatives

Seven benzylamino derivatives of podophyllotoxin 8a–8g were synthesized and their chemical structures were confirmed by IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectral analyses. Their abilities to inhibit the growth of cancer cells A549, HCT‐116 and HepG2, were investigated by MTT assay. Compound 8b possessed the highest cytotoxicity on cancer cell lines with average IC₅₀ values of 3.8 µM. All we synthetic compounds were cytotoxic against three cancer cell lines at the micromolar range, indicating podophyllotoxin derivatives with structural modification of benzylamino possess potent antitumor activity.     

Synthesis and antimicrobial activities of 5-fluoro-1,2,6-trisubstituted benzimidazole carboxamide and acetamide derivatives

Some 5-fluoro-6-substitute-1 H-benzimidazole-2-carbamates (12a-e), 5-fluoro-6-substituted 1H-benzimidazole-2-acetate (13a-e) and 2-acetamide (14a-f) derivatives, 2-acetamido-5-fluoro-6-(morpholin-4-yl)-1-propyl-1H-benzimidazole (15), and 1-cyclopropyl-2-ethyl-5-fluoro-6-(4-methylpiperazin-1-yl)- 1H-benzimidazole (16) were synthesized, and their antimicrobial and antifungal activities evaluated. Compound 12c exhibited the best activity against Candida albicans.     

Dose- and time-dependent effects of doxorubicin on cytotoxicity,cell cycle and apoptotic cell death in human colon cancer cells

The cytostatic drug doxorubicin is a well-known chemotherapeutic agent which is used in treatment of a wide variety of cancers. A key factor in the response of cancer cells to chemotherapeutic drugs is the activation of the apoptotic pathway, a pathway that is often impaired in chemoresistant colon cancer cells. The aim of the present study was to investigate the effects of doxorubicin in Hct-116 human colon carcinoma cells in order to clarify if a time/concentration range for optimal doxorubicin-induced apoptosis exists. We compared a treatment schedule were cells were bolus incubated for 3 h with doxorubicin followed by 24 h in drug-free medium, with a continuous doxorubicin treatment schedule for 24 h. Bolus incubation was carried out to determine effects of doxorubicin accumulated during the first 3 h, whereas continuous incubation allowed further (continuous) exposure to doxorubicin. We found that bolus (3 h) treatment with doxorubicin resulted in a dose-dependent decrease of viable cells and concomitant increase of apoptosis. Additionally, bolus (3 h) doxorubicin incubation led to phosphorylation of p53 at serine 392, induction of p21, G2 arrest and increase of proapoptotic protein Bax. In contrast, continuous (24 h) treatment with doxorubicin reduced the number of living cells with no parallel raise in the amount of dead cells. Continuous (24 h) treatment with 5 μM doxorubicin resulted in cell cycle arrest in G0/G1 phase that was neither accompanied by phosphorylation and activation of p53 nor enhanced expression of p21. These results suggest that doxorubicin is able to induce cell death by apoptosis only at particular dose and treatment conditions and imply a completely different cellular response following bolus or continuous exposure to doxorubicin.     

Synthesis,characterization and biological activity of a series of carboxamide derivatives of ofloxacin

The present study was designed to help develop new agents with better antimicrobial profiles. Specifically, we focused on modification of the basic structure of ofloxacin by introducing new functionality at its C3 position. For this purpose, the carboxylic group at the C3 position of ofloxacin was replaced by an amide group through an ester aminolysis reaction. The structure of these derivatives was established by various analytical techniques i.e., IR, ¹H-NMR, ¹³C-NMR CHNS elemental analysis and mass spectrometry. The antibacterial activity of ofloxacin and its derivatives against ten different Gram-positive and Gram-negative microorganisms was studied using a disk susceptibility method. These compounds were further tested for their activity against various fungi and compared to ofloxacin. The synthesized compounds showed diverse antimicrobial profiles. Among them, a few compounds possessed a comparable or better activity in comparison to the reference drug.     

Synthesis and selective cytotoxicity of novel biphenyl-based tetrazole derivatives

Cancer today represents a significant public health problem worldwide, and the challenge is to produce cost-effective drugs. Recently, biphenyl compounds as well as tetrazole derivatives is known for their potential non-selective anticancer activities. In search of novel selective anticancer agents, a series of newly hybrid molecules was designed and synthesized by combining the structural features of biphenyl and tetrazole moieties. The structures of newly synthesized compounds were characterized using spectroscopic techniques (FT-IR, ¹H NMR, ¹³C NMR, and HMBC). Cytotoxic evaluations of these novels compound on human cancer cell lines showed a significant anticancer activity against more than one tested cell lines. Compounds 5n, 5j, and 5o proved to exhibit the strongest and selective cytotoxic effect on HepG2 and MCF-7 lines. Taken together, this study has led to the development of promising leads for cancer therapy.     

聚天冬酰胺衍生物的合成及细胞毒性研究

目的 合成一种聚天冬酰胺衍生物并对其细胞水平的安全性进行评价, 为其作为药物载体应用提供研究基础。方法 通过 L-天冬氨酸热缩聚合成聚琥珀酰亚胺, 利用苯丙氨酸甲酯盐酸盐和乙醇胺对聚琥珀酰亚胺进行开环反应得到载体 PSI-Phe-EA; 利用 1H NMR 进行聚合物结构表征; 采用内标法磁氢谱计算其开环率; 通过水溶性的比较验证其亲水性变化; 采用 MTT 法对聚合物的细胞增殖抑制进行研究, 利用倒置显微镜观察聚合物对细胞微观形态的影响; 利用碘化丙啶 （PI） 染色法通过流式细胞仪研究聚合物对细胞周期的影响。结果 1H NMR 确证了开环衍生物 PSI-Phe-EA 的结构, PSI 的开环率为 40%; 乙醇胺开环后聚合物的亲水性得到了明显改善; MTT 实验表明,PSI-Phe-EA 在所检测浓度范围内 （<100 mg/L）, 对 NIH3T3 和 HepG2 两种细胞的 24 h 细胞存活率均在 80%以上; 倒置显微镜观察表明, 50 mg/L 的 PSI-Phe-EA 孵育 24 h 后以上两种细胞的形态与对照组无明显差异; 细胞周期分析表明 PSI-Phe-EA 处理与否对细胞周期分布的影响无明显差异。结论 合成的聚天冬酰胺衍生物PSI-Phe-EA 亲水性明显提高, 且对细胞的存活、 微观形态以及周期分布均无明显影响, 是一种安全的高分子材料。     

Synthesis of 4'-hydroxy-3'-piperidinomethylchalcone derivatives and their cytotoxicity against PC-3 cell lines

A new series of mono Mannich bases of 4'-hydroxychalcones 2a-e carrying a variety of aryl groups was synthesized and the in vitro cytotoxic activities of the new compounds were screened against PC-3 cell lines. Bioactivities of 2a-e, which are reported for the first time in this study, were compared against their precursor 4'-hydroxychalcones 1a-e. Compound 2b was found to be the most potent (IC(50 )= 3.7 microM) among the compounds synthesized. In addition, the compounds 1a-c and 2d showed moderate cytotoxicity. Incorporation of the 3'-piperidinomethyl group in 1b and 1d raised the potency by 1.68 and 2.19 times respectively and, therefore, seemed to be a noteworthy molecular modification. Correlations were noted between cytotoxicity and one or more physiochemical constants of the aryl ring as well as log P values for the compounds 2a-e. The significant improvement of cytotoxicity of 2b, 2d, and 2e against PC-3 cell lines compared with their chalcone precursors suggests that the incorporation of a piperidinomethyl group is a useful molecular modification and further development of these compounds as candidate cytotoxic agents may be warranted.     

Synthesis and anticholinesterase activity and cytotoxicity of novel amide derivatives

In the present study, some amide derivatives were synthesized and their potential anticholinesterase properties were investigated. N-(Benzothiazol-2-yl)-2-[(5-amino/methyl-1,3,4-thiadiazol-2-yl)thio]acetamide derivatives were obtained by nucleophilic substitution of 2-chloro-N-(benzothiazole-2-yl)acetamide derivatives with appropriate 1,3,4-thiadiazole-2-thioles. The chemical structures of the compounds were elucidated by (1) H-NMR, (13) C-NMR and FAB(+) -MS spectral data and elemental analyses. Each amide derivative was evaluated for its ability to inhibit AChE and BuChE using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. 2-(5-Amino-1,3,4-thiadiazol-2-yl)thio-N-(benzothiazol-2-yl)acetamide derivatives have anticholinesterase activity, whereas 2-(5-methyl-1,3,4-thiadiazol-2-yl)thio-N-(benzothiazol-2-yl)acetamide derivatives have no inhibitory effect on enzyme activity. Among these compounds, it is clear that compound IIh is the most potent derivative.     

Synthesis and cytotoxic activity of carboxamide derivatives of benzo[b][1,6]naphthyridines

The reaction of 4-dimethylaminomethylene-6-methyl-4H-pyrano[4,3-b]quinoline-1,3-dione with a range of primary amines gave rise to a series of 2-substituted 6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acids. The derived 4-N-[2-(dimethylamino)ethyl]carboxamides were tested for growth inhibitory properties against murine P388 leukemia, Lewis lung carcinoma (LLTC), and human Jurkat leukemia cell lines. Most compounds were potent cytotoxins, with some having IC(50) values less than 10 nM. Five were tested in vivo against subcutaneous colon 38 tumors in mice, and a single dose (3.9 mg/kg) proved to be curative for the 2-methyl and 2-(3,4-dimethoxyphenyl) derivatives in this refractory model.     

Synthesis and cytotoxicity of novel 3-amino-4-indolylmaleimide derivatives

In an attempt to develop potent and selective antitumor agents, a series of novel 3-amino-4-indolylmaleimides were designed and synthesized. The reaction showed high regioselectivity. The structure of compound 7a was determined by an X-ray single crystal diffraction method. The cytotoxicities of the title compounds were evaluated against HeLa, SMMC 7721 and HL 60 cancer cell lines by a standard MTT assay in vitro. The pharmacological results showed that some of the title compounds displayed moderate or high cytotoxic activity against the tested cell lines. Compound 7d was the most promising compound against the tested cancer cell lines. Structure-activity relationships are discussed based on the experimental data obtained. A hydroxyethylamino group at the 3-position in the side chain of indolylmaleimide is associated with an increase in cytotoxicity.     

Synthesis and cytotoxicity evaluation of some 8-hydroxyquinoline derivatives.

Interest in Mannich bases of 8-hydroxyquinoline stems from reports of their high potency against human cancer cells. In the search for potential anticancer drug candidates, Mannich bases of 8-hydroxyquinoline (7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline, 7-piperidinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline) were synthesised by reaction with various secondary amines and formaldehyde. They were prepared as hydrochlorides. The cytotoxic activity of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline compounds in the National Cancer Institute in-vitro cancer cell line panel was determined. It was found that they exhibited substantial cytotoxic activity against leukaemia. The log concentration of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline that inhibited 50% of 60 cell lines' growth were -4.81 M, -5.09 M and -5.35 M, respectively. Compound 7-pyrrolidinomethyl-8-hydroxyquinoline was selected for further in-vivo testing. The electrophysiological effect of 7-pyrrolidinomethyl-8-hydroxyquinoline also was tested in human myeloma cells (RPMI 8226). The outward current was voltage dependent, activating at -40 mV and believed to be the voltage-activated K+ current I(K(V)). 7-Pyrrolidinomethyl-8-hydroxyquinoline (1-30 microM) caused the inhibition of I(K(V)) in a concentration-dependent manner. The IC50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of I(K(V)) is 23 microM. The GI50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of cell growth is 14 microM. The results suggest that at least part of the cytotoxicity effect of 7-pyrrolidinomethyl-8-hydroxyquinoline on myeloma cells could be related to blockade of voltage-activated K+ channels.     

Synthesis,cytotoxicity, and DNA-binding property of berberine derivatives

9-Substituted berberine derivatives (4a–4f) with polyethylene glycol side chain and terminal group were synthesized and characterized by elemental (C, H, and N) and spectral analysis (NMR, HRMS and FTIR). These compounds were tested for their in vitro cytotoxic activity against four human tumor cell lines: granulocyte leukemia (HL-60), gastrocarcinoma (BGC-823), carcinoma (Bel-7402), and nasopharyngeal carcinoma (KB) by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The DNA-binding properties were investigated by UV–Vis absorption, fluorescence, CD spectroscopies, and thermal denaturation measurements. The results indicated that 4a–4f exerted cytotoxic effects with selectivity against tested cell lines. 4a exhibited higher cytotoxicity than cisplatin, berberine, and berberrubine against HL-60 and BGC-823 cell lines. The length of side chains and nature of terminal groups played an important role in the cytotoxicity. Berberine derivatives binded to CT-DNA in an intercalating mode. The binding affinities decreased with the increasing length of side chains. Compounds 4a–4c and 4e could change the DNA conformation from B to A-like form.     

Synthesis and in vitro cytotoxicity evaluation of novel naphthindolizinedione derivatives

Novel 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxamide derivatives and the corresponding 7,10-dihydroxy analogues were designed in accordance with Moore's and Pindur's theory and synthesized based on the structural similarity with known antitumour agents such as ellipticine, daunorubicin, mitoxantrone and 9-aminoacridine-4 carboxamide derivatives. These compounds, including structural variations of the amide side chain, were evaluated in the NCI panel of human tumour cell lines, from which 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-(2-dimethylamino-ethyl)-12-carboxamide 11a was found to be the most potent agent within the series. It showed good selectivity towards leukaemia, colon and renal cancer cell lines, with significant GI50 values, from lower than 10 nM to 0.2 microM. Moreover, its cytotoxicity against the adriamicine-resistant breast tumour cell line at a concentration lower than 1 microM turned out to be higher than the values using the clinical anticancer agents, daunorubicin and mitoxantrone.