Discovery and structure–activity relationship of plastoquinone analogs as anticancer agents against chronic myelogenous leukemia cells

Two series of amino‐1,4‐benzoquinones ( AQ1–18 ) based on the structural analogs of plastoquinones were synthesized and the structure–activity relationship against chronic myelogenous leukemia activity was examined. All of the synthesized compounds were tested for their cytotoxic effects on different leukemic cell lines. Of interest, AQ15 exhibited a better selectivity than the reference drug imatinib on cancer cells. Owing to this, AQ15 was selected for a further apoptosis/necrosis evaluation where AQ15 ‐treated K562 cells demonstrated similar apoptotic effects like imatinib‐treated cells at their IC₅₀ values. The inhibitory effects of AQ15 and the other three compounds with various activities against eight tyrosine kinases, including ABL1, were investigated. AQ15 showed weak activity against ABL1, and a correlation was observed between the anti‐K562 and anti‐ABL1 activities. The binding mode of AQ15 into the ATP binding pocket of ABL1 kinase was predicted in silico, showing the formation of some key interactions. In addition, AQ15 was shown to suppress the downstream signaling of BCR‐ABL in K562 cells. Finally, AQ15 obviously cleaved DNA in the presence of an iron(II) complex system, indicating that this can be the major mechanism of its antiproliferative action, whereas the mild inhibition of ABL kinase is just in‐part mechanism of its overall outstanding cellular activity.     

Design,synthesis, and evaluation of new series of Imperatorin analogs with potential vasodilatory activity

Two series of imperatorin analogs were synthesized based on our previous research and evaluated for their vasodilatation activities on in vitro rat mesenteric artery, basilar artery, and renal artery ring models. Target compounds were characterized by infrared, ¹H NMR, and mass spectra. Most derivatives possessed significant vasodilatory activity on the mesenteric artery, and compound 3a exhibited favorable and broad vasodilatation activities on three kinds of rat artery ring models. The pharmacological results indicated that introducing nitrogen-contained ring in side chain or large steric hindrance at the distal end could increase the vasodilatory activity. Further, replacement of oxygen atom (–O–) in the skeleton of furocoumarin derivatives with nitrogen (–NH–) could cause the decrease of vasodilatory activity. The molecular docking also indicated that compound 3a showed a best affinity with α-1C receptor (PDB ID: 3G43). All these results suggested compound 3a would be a potential vasodilatory agent for hypertension.     

Design,synthesis, docking study and cytotoxic activity evaluation of some novel letrozole analogs

Background

Breast cancer is the most common type of female cancer. One class of hormonal therapy for breast cancer drugs -non steroidal aromatase inhibitors- are triazole analogues. In this work, some derivatives of these drugs was designed and synthesized. All synthesized compounds were evaluated for their cytotoxic activities on breast cancer cell lines (MDA-MB-231, T47D and MCF-7).

Methods

Our synthetic route for designed compounds started from 4-bromotolunitrile which was reacted with 1H-1,2,4-triazole to afford 4-(4-cyanobenzyl)-1,2,4-triazole. The reaction of later compound with aromatic aldehydes led to formation of the designed compounds. Eleven novel derivatives 1a-k were tested for their cytotoxic activities on three human breast cancer cell lines.

Results

Among the synthesized compound, 4-[2-(3-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1c) showed the highest activity against MCF-7 and MDA-MB-231 cell lines and 4-[2-(4-methoxyphenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 h) exhibited highest activity against T47D cell line. According to cytotoxic activities results, compound 4-[2-(4-dimethylamino)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 k) showed comparative activity against T47D and MDA-MB-231 cell lines with compound (1 h) and our reference drug Etoposide.

Conclusion

In the process of anti-cancer drug discovery, to find new potential anti-breast cancer agents, we designed and synthesized a novel series of letrozole analogs. Cytotoxicity evaluation revealed that compounds (1c) and (1 k) were the most potent compounds with comparative activity with Etoposide. The results revealed that π-π interactions are responsible for the enzyme inhibitions of compounds (1 c) and (1 k).Keyword: Breast cancer, Non-steroidal aromatase inhibitor, Cytotoxic activity     

Design,synthesis, and cytostatic activity of novel pyrazine sorafenib analogs

The current study is focused on a series of sorafenib analogs as potential antitumor agents. We have designed and synthesized nine novel pyrazine analogs 6a–i differing in amide and/or urea regions. Two alternative strategies for the preparation of title compounds were applied. The first strategy involved ether formation between 4-hydroxyphenyl urea 3 and 5-chloro-pyrazine-2-carboxamides 4. In the second strategy, ether functionality was introduced in the molecule before urea moiety and included preparation of 5-(4-aminophenoxy)-N-alkylpyrazine-2-carboxamides 5 and their reaction with 4-chloro-3-(fluoromethyl)phenyl isocyanate. Cytostatic activity of the title compounds was evaluated in vitro against a panel of cancer cell lines. Most of the tested compounds showed strong antiproliferative activity in the low micromolar range. 5-/4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy/-pyrazine-2-carboxylic acid (4-chloro-3-trifluoromethylphenyl)-amide (6g) was the most active compound (IC₅₀ 0.9–7.5?μM) and showed comparable or stronger activity than sorafenib, but also similar cytotoxicity to normal human fibroblast cells. Two compounds, namely, 5-/4-[3-(4-bromophenyl)-ureido]-phenyloxy/-pyrazine-2-carboxylic acid cyclopentylamide (6c) and 5-/4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy/-pyrazine-2-carboxylic acid cyclopentylamide (6h), exerted cytostatic activities that surpassed the effects observed with sorafenib in three cancer cell lines (HepG2, HeLa, A549, IC₅₀ 0.6–0.9?μM). Similar to sorafenib, compound 6h proved to be cytotoxic to normal human fibroblast cells, whereas compound 6c did not diminish proliferative capacity of these cells and could be regarded as the most promising derivative. Additional biological studies on the c-Raf activity using Western blot method revealed that antiproliferative activity of 6h could be at least partially attributed to its inhibitory effect on c-Raf activation similar to sorafenib. In contrast, 6c did not inhibit the activity of c-Raf, which implies that other cell signaling pathways govern its antiproliferative effects. Taking into account structural differences between compounds 6c and 6h, it is plausible to believe that the substituent in urea part of the molecule is essential for the interaction with c-Raf.     

Design, synthesis and evaluation of novel rhodanine-containing sorafenib analogs as potential antitumor agents

A series of rhodanine-containing sorafenib analogs was designed, synthesized and evaluated for their in-vitro antitumor activity against three cancer cell lines (A549, H460 and HT29). Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity superior to the reference drug sorafenib, especially the most promising compound 7r (with the IC(50) value of 0.8, 1.3 and 2.8 μM against A549, H460 and HT29 cell lines, respectively). The activity was found to strongly depend on the substitution pattern of the rhodanine motif at C-5″ position. Results suggested that this series of compounds could serve as the bases for the development of novel antitumor agents.     

Design,synthesis, and biological characterization of tamibarotene analogs as anticancer agents

In our efforts of developing novel compounds as potential anticancer agents, a series of tamibarotene analogs containing Zn²⁺‐binding moieties were designed and developed. Biological characterization identified compound 7b as the most potent one with improved antiproliferative activities against multiple cancer cell lines, compared to parent compound tamibarotene. Further characterization also demonstrated that compound 7b exhibited moderate activities as a histone deacetylase inhibitor with IC₅₀ of 1.8 ± 0.1 μm , thus suggesting that this could contribute to the improved antiproliferative activities of 7b . Pharmacokinetic studies revealed that compound 7b could release tamibarotene after administration and prolong the circulation time of tamibarotene, and this may also potentially contribute to the improved antiproliferative activities. Collectively, the results demonstrated that compound 7b could serve as a new lead for further development of more potent analogs as potential anticancer agents.     

一系列新型虫草素衍生物的设计、合成及其抗肿瘤活性研究

本研究合成了一系列6位嘌呤环取代苯磺酰胺基团的虫草素衍生物,并对其进行了抗肿瘤活性研究.我们对虫草素衍生物具有抗肿瘤活性的药效结构部分做了初步探讨.在MDA-MB-231和A549细胞的抗增殖活性实验中,苯环上有4-甲基和4-硝基取代基的化合物活性优于先导化合物.然而,在HeLa细胞的抗增殖活性实验中,4-甲氧基苯、2...     

Design,synthesis and biological evaluation of novel thiophene and theinopyrimidine derivatives as anticancer agents

Some novel thiophene and theinopyrimidine derivatives have been synthesized. Their structures were confirmed by elemental analyses, infrared, ¹H NMR, ¹³C NMR and mass spectral data. All the target compounds were screened against liver adenocarcinoma (HepG2) cell line. Compounds 9c, 9b, 10b, and 7c in a sequent were the most potent compounds between all the test compounds with IC₅₀ values [0.01063, 0.01158, 0.01729, 0.01957?µM], respectively. Compounds 13b, 7b, 5d, 9a, 8a, and 11b showed higher activity with IC₅₀ values ranged from 0.02231 to 0.03673?µM when compared with 5-flurouracil (A) as a reference drug (IC₅₀?=?0.0384?µM).     

二苯并呋喃类化合物的设计合成及血管生成抑制作用

目的 寻找具有抗血管生成作用的二苯并呋喃类化合物并探讨其初步构效关系。方法 以苯酚类化合物、1,3-环己二烯为原料在对甲苯磺酸的催化下反应得到烷基化产物（2-环己烯基）-苯酚类化合物2a~2e和环合产物六氢二苯并呋喃类化合物3a~3e;2a~2e在二（氰基苯）二氯化钯作用下环合得到1,2,3,4-四氢二苯并呋喃类化合物4a~4e。以HUVEC、A549、Bel-7402和MCF-7为测试靶细胞,采用MTT法对目标化合物进行体外抑制内皮细胞和肿瘤细胞增殖的活性筛选。结果 共合成了10个目标化合物,其结构经¹H-NMR、¹³C-NMR、MS谱确证,化合物3b~3e和4b~4e为新化合物。其中,化合物4c和4e对HUVEC具有良好的抑制作用并且对HUVEC细胞具有显著的选择性。结论 苯环上的羟基、烷基取代以及它们的取代位置对抑制HUVEC增殖有重要影响;[4a,9a] 的碳碳双键可能对化合物抑制HUVEC增殖有一定的提高作用。     

Design, synthesis, and biological evaluation of (E)-styrylbenzylsulfones as novel anticancer agents

Cell cycle progression is regulated by cyclins and cyclin-dependent kinases, which are formed at specific stages of the cell cycle and regulate the G1/S and G2/M phase transitions, employing a series of "checkpoints" governed by phosphorylation of their substrates. Tumor development is associated with the loss of these checkpoint controls, and this provides an approach for the development of therapeutic agents that can specifically target tumor cells. Here, we describe the synthesis and SAR of a novel group of cytotoxic molecules that selectively induce growth arrest of normal cells in the G1 phase while inducing a mitotic arrest of tumor cells resulting in selective killing of tumor cell populations with little or no effect on normal cell viability. The broad spectrum of antitumor activity in vitro and xenograft models, lack of in vivo toxicity, and drug resistance suggest potential for use of these agents in cancer therapy.     

Synthesis,antitumor activity evaluation,and DNA‐binding study of coumarin‐based agents

A novel series of coumarin‐thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, ¹H NMR, ¹³C NMR, mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60‐cell line panel according to the US NCI‐DTP protocol or a selection of human tumor cell lines: breast cancer (MCF‐7), liver cancer (HepG‐2), and colorectal cancer (HCT‐116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with K_SV = 4.27 × 10⁵ M^?1. Moreover, the results for compounds 8 , 4c , and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with K_SV 4.27 × 10⁵, 3.96 × 10⁵, and 3.51 × 10⁵ M^?1, respectively, compared to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60‐cell line panel, the leukemia HL‐60 cell line was the most susceptible to growth inhibition when treated with 14a , resulting in 61% growth, followed by the lung carcinoma cell line NCI‐H522 showing 67% growth when treated with 9 . Moreover, compound 10c had an IC₅₀ value of 24.9 μg/mL against the HepG‐2 cell line.

     

Preclinical efficacy of ST1976, a novel camptothecin analog of the 7-oxyiminomethyl series

In previous studies, we have documented the potential therapeutic advantages of camptothecin analogs modified at the 7-position, i.e., 7-oxyiminomethyl derivatives. The present study was performed to explore the therapeutic potential of novel hydrophilic derivatives of this series. With one exception (ST1976), the tested camptothecins exhibited a reduced antiproliferative activity and all compounds retained ability to stabilize the topoisomerase I-mediated cleavable complex. The two analogs (ST1976 and ST1968) characterized by the presence of a free amino group in the side chain also exhibited the formation of persistent cleavable complexes. The most potent compound, ST1976 (7-(4-aminobenzyl)oxyiminomethylcamptothecin), was selected for evaluation of its preclinical profile of antitumor activity in a large panel of human tumor xenografts. As expected on the basis of the introduction of a hydrophilic substituent, the novel camptothecin was a substrate for BCRP. However, in spite of an apparent recognition by BCRP, ST1976 was effective following oral administration. The antitumor activity was evaluated using various schedules and routes of administration (i.v. and p.o.). ST1976 exhibited a remarkable activity in all tested tumors and was effective in a number of tumors which are resistant to irinotecan. The biological and pharmacological profile of ST1976 supports the therapeutic potential of camptothecins containing hydrophilic substituents at the 7-position. On the basis of its excellent activity in preclinical models, ST1976 is a promising candidate for clinical development.     

Design,synthesis, cytotoxicities and DNA cleavage activities of dibenzoxepine and isoquinoline derivatives starting from dehydroabietylamine

A series of novel hexahydrodibenzoxepine and quinazoline derivatives were designed and synthesized starting from dehydroabietylamine. The cytotoxicities of the compounds against L02 and HepG2 cell lines were investigated. Meanwhile, the plasmid DNA (Escherichia coli) cleavage of several heterocyclic derivatives was studied. These compounds exhibit remarkable activities on plasmid DNA pBR322. Our study provides useful information for developing new and more potent antitumor agents.     

5-氟尿嘧啶类衍生物的设计、合成及其抗肿瘤活性研究

目的合成一系列含5-氟尿嘧啶(5-FU)结构的衍生物并对此类化合物进行抗肿瘤活性研究。方法以5-FU为起始原料,通过加成、缩合,与邻硝基苯氧乙酸类载体通过酯化反应得到目标化合物,并用1H-NMR和MS确证其结构。MTT法检测目标化合物对细胞A549、Hep G 2、He La和正常细胞WI-38的抑制作用。结果目标化合物对肿瘤细胞均有一定的抑制活性,尤其是化合物9对细胞A549的抑制作用[IC50=(3.04±0.48)μmol·L-1]明显优于阳性对照5-FU[IC50=(49.81±1.49)μmol·L-1],且对于正常细胞的毒副作用较小。结论该合成路线所需反应条件温和,便于操作,且目标化合物9具有较好的抗肿瘤活性,值得进一步研究。     

大黄素季铵盐类衍生物的设计合成与抗癌活性评价

通过大黄素的3位烷基化,1位保护及与叔胺反应实现了对大黄素的化学修饰.目标产物是一个季铵盐.测试了目标产物对白血病细胞Molt-4和人淋巴瘤细胞CA46的抗癌活性.结果表明目标产物的抗癌活性比大黄素约高10倍.     

Conversional synthesis and cytotoxic evaluation of novel taxoid analogs

Four novel taxoid analogs were conversionally synthesized from the C₁₉-diterpenoid alkaloid deltaline, and their cytotoxic activities were evaluated against a small panel of cancer cell lines.     

Conversional synthesis and cytotoxic evaluation of novel taxoid analogs

Four novel taxoid analogs were conversionally synthesized from the C(19)-diterpenoid alkaloid deltaline, and their cytotoxic activities were evaluated against a small panel of cancer cell lines.     

Design, synthesis and anticonvulsive activity of analogs of gamma-vinyl GABA

For the development of new anticonvulsive agents, analogs of gamma-vinyl GABA (vigabatrin) containing GABA, gamma-vinyl GABA, valproic acid, nipecotic acid or isonipecotic acid moieties were prepared and evaluated for their anticonvulsive activities. Most of the prepared compounds showed moderate anticonvulsive activities. Among them compounds 10 and 16 displayed the most potent anticonvulsive activity and a broader spectrum compared to vigabatrin.     

Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpyrazole derivatives

Aim: To design and synthesize a series of novel amino acid-binding 1,5-diarylpyrazole derivatives, which are intended to act as prodrugs with better aqueous solubility than celecoxib, and which will exert potent anti-inflammatory activi-ties after being converted to their parent compounds in vivo. Methods: To introduce an amino acid, celecoxib analogs containing amino or methylamino group were synthesized first through multi-step chemical reactions. All the synthesized compounds were screened in an intact cell-based assay in vitro and in carrageenan-induced mouse paw edema in vivo. Some active compounds were selected for further evaluation in a carrageenan-induced rat paw edema model. The preliminary pharmacokinetics experiments were conducted using high performance liquid chromatography/mass spectrometry (HPLC/MS). Results: Celecoxib, 6 of the 1,5-diarylpyrazole class of celecoxib analogs, and their amino acid derivatives (hydrochloride salts) were synthesized. In vitro screening, the hydrochloride salts showed decreased inhibitory effects on cyclooxygenase (COX)- 1 and COX-2 compared with their parent compounds, but some exhibited potent anti-inflammatory activity in vivo. Compound 4a was selected for further evaluation, and its anti-inflammatory effect was equivalent to that of celecoxib after oral administration in the carrageenan-induced rat paw edema model. At three doses (25 mg/kg, 50 mg/kg, and 100 mg/kg) the percentage inhibition on edema was 20.7%, 52.6%, and 62.6% (for compound 4a) and 27.8%, 38.4%, and 40.1% (for celecoxib), respectively. Preliminary pharmacokinetic evaluations support the hypothesis that compound 4a was actually converted to its parent compound, compound 4. Conclusion: The compound bound with amino acid acts like prodrug, which can exert anti-inflammatory effect similar to celecoxib after being converted to its parent compound. This finding will be of great benefit in carrying out structural modifications of prodrug-like selective COX-2 inhibitors.