Synthesis of Murrayaquinone-A Derivatives and Investigation of Potential Anticancer Properties

A series of novel murrayaquinone a derivatives were synthesized and their anti-cancer activity were evaluated on healthy colon cell lines (CCD-18Co), primary (Caco-2) and metastatic (DLD-1) colon cancer cell lines. The results showed that the cytotoxicity of murrayaquinone molecules is significantly high even in micromolar levels. The DNA binding, cell cycle arrest and metabolic activity studies of these molecules were also carried out and the results showed that these molecules induce apoptosis. In conclusion, the data support further studies on murrayaquinone derivatives toward selection of a candidate for cancer treatment.     

Arylpropionic acid-derived NSAIDs: New insights on derivatization,anticancer activity and potential mechanism of action

NSAIDs displayed chemopreventive and anticancer effects against several types of cancers. Moreover, combination of NSAIDs with anticancer agents resulted in enhanced anticancer activity. These findings have attracted much attention of researchers working in this field. The 2-arylpropionic acid-derived NSAIDs represent one of the most widely used anti-inflammatory agents. Additionally, they displayed antiproliferative activities against different types of cancer cells. Large volume of research was performed to identify molecular targets responsible for this activity. However, the exact mechanism underlying the anticancer activity of profens is still unclear. In this review article, the anticancer potential, structure activity relationship and synthesis of selected profen derivatives were summarized. This review is focused also on non-COX targets which can mediate the anticancer activity of this derivatives. The data in this review highlighted profens as promising lead compounds in future research to develop potent and safe anticancer agents.     

Indenoindolone derivatives as topoisomerase II–inhibiting anticancer agents

Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II–inhibiting anticancer agents. They are hydrazones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with suitable substitutions exhibited potent specific inhibition of human DNA TopoIIα while not showing inhibition of topoisomerase I and DNA intercalation, despite the fact that parent indenoindolones are known poor/moderate inhibitors of topoisomerase II. The potent topoisomerase II inhibitor indenoindolone derivatives exhibited good anticancer activities compared to etoposide and 5-fluorouracil, and relatively low toxicity to normal cells. These derivatizations of indenoindolones were found to result in enhancement of anticancer activities.     

Decision making for promising quinoline‐based anticancer agents through combined methodology

During the development of effective drugs for the treatment of cancer, one of the most important tasks is to identify effective drug candidates having maximum antiproliferation and minimum side effects. This paper considers the problem of selecting the most promising anticancer agents, showing inhibition at low IC₅₀ concentration and low releasing lactate dehydrogenase percentage (cytotoxicity). Recently, we prepared quinoline analogs bearing different functional groups and determined their anticancer potential against the HeLa, C6, and HT29 cancer cell lines using different anticancer assays. Experimentally, seven quinoline derivatives consisting of different substituents were determined as promising anticancer agents. We propose a multicriteria recommendation method to identify the most promising anticancer agents against all tested cell lines with an accurate prediction algorithm according to the available input data. A multicriteria decision‐making methodology (MCDM) was used for the solution of the relevant problem in this study. Both the experimental results and MCDM method indicated that 5,7‐dibromo‐8‐hydroxyquinoline ( 2 ) and 6,8‐dibromo‐1,2,3,4‐tetrahydroquinoline ( 6 ) are the most promising anticancer agents against the HeLa, HT29, and C6 cell lines.     

Benzothiazole derivatives as anticancer agents

Abstract

Benzothiazole (BTA) belongs to the heterocyclic class of bicyclic compounds. BTA derivatives possesses broad spectrum biological activities such as anticancer, antioxidant, anti-inflammatory, anti-tumour, antiviral, antibacterial, anti-proliferative, anti-diabetic, anti-convulsant, analgesic, anti-tubercular, antimalarial, anti-leishmanial, anti-histaminic and anti-fungal among others. The BTA scaffolds showed a crucial role in the inhibition of the metalloenzyme carbonic anhydrase (CA). In this review an extensive literature survey over the last decade discloses the role of BTA derivatives mainly as anticancer agents. Such compounds are effective against various types of cancer cell lines through a multitude of mechanisms, some of which are poorly studied or understood. The inhibition of tumour associated CAs by BTA derivatives is on the other hand better investigated and such compounds may serve as anticancer leads for the development of agents effective against hypoxic tumours.     

Synthesis of 2-,4,-6-, and/or 7-substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents: 3D QSAR-assisted design

Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC₅₀ value of 1.56?µM and 1.22?µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.     

Apoptosis induction in HL-60 cells and inhibition of topoisomerase II by triterpene celastrol

Celastrol, which is a triterpene purified from Celastraceae plants, has anticancer and anti-inflammatory activities. In this study we investigated to clarify whether celastrol can induce apoptosis in a human leukemia HL-60 model system. Celastrol was found to induce apoptosis, and the rank order of the potency of celastrol and its derivatives to induce internucleosomal DNA fragmentation was found to be celastrol>cela-H>the other derivatives=vehicle control. Many anticancer agents are known to possess the ability to inhibit topoisomerase II, so the inhibitory activities of celastrol and its derivatives on topoisomerase II were also explored. The rank order of the inhibitory activity was found to be celastrol>etoposide>cela-H, indicating that the apoptosis-inducing activities of cela derivatives correspond to their inhibitory activities on topoisomerase II. These data suggested that celastrol may cause its effects such as anticancer activity by the mechanism of apoptosis along with topoisomerase II inhibition.     

Pyrazolo[4,3-d]pyrimidines as new generation of cyclin-dependent kinase inhibitors

A search among analogues of anti-CDK purines led to the identification of substituted pyrazolo[4,3-d]pyrimidines as novel inhibitors of CDK1/cyclin B. Some of these derivatives also show antiproliferative activity on cancer cell line K-562, thus may find an application as anticancer agents.     

Novel matrix metalloproteinase inhibitors derived from quinoxalinone scaffold (Part I)

A series of quinoxalinone peptidomimetic derivatives was designed, synthesized, and assayed for their inhibitory activities on metalloproteinase-2 (MMP-2) and aminopeptidase N (APN). The results showed that all of these quinoxalinone derivatives displayed highly selective inhibition against MMP-2 as compared with APN, with IC₅₀ values in the micromole range. Compound A3 showed comparable MMP-2 inhibitory activities than the positive control LY52, which might be used as a potential lead in future research on anticancer agents.     

Synthesis and biological evaluation of novel thioapio dideoxynucleosides

On the basis of the bioisosteric rationale to apio dideoxynucleosides, novel thioapio dideoxynucleosides have been synthesized, starting from 1,3-dihydroxyacetone via thioapio sugar acetate as a key intermediate. The intermediate was condensed with silylated pyrimidine bases such as N(4)-benzoylcytosine, uracil or thymine in the presence of TMSOTf to give the beta-anomers and alpha-anomers, respectively. The intermediate was also condensed with silylated 6-chloropurine to give the 6-chloropurine derivatives and which were converted to adenine derivatives and, N(6)-methyladenine derivatives and, and hypoxanthine derivatives and, respectively. The guanine analogues and were also synthesized from the condensation of sugar acetate with 2-acetamido-6-chloropurine. All synthesized final compounds were tested against HIV-1. Most of the synthesized compounds exhibited toxicity-dependent anti-HIV-1 activity, among which 6-chloropurine derivative was found to be the most cytotoxic and showed good cytotoxicity against colon cancer cell lines. Although we could not find good anti-HIV agents in this study, findings of some anticancer activity in this series will allow this class of nucleosides to be the new template for the development of new anticancer agents (Fig. 1).     

Synthesis and antiproliferative activity of benzocyclobutacarbazol derivatives. A new class of potential antitumor agents

Several benzocyclobutacarbazol derivatives were synthesized and evaluated for their potential cytotoxic properties. A number of these compounds exhibited significant antiproliferative activity with concomitant interaction with the cell cycle and represent a new class of potential anticancer agents.     

Synthesis, anticancer and antioxidant activities of some novel N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives

A series of N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives were synthesized by treating N-(benzoxazol-2-yl)hydrazinecarboxamide with different isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral analyses. All the synthesized derivatives (Va-l) were screened for anticancer and antioxidant activities. The results showed the anticancer activity of test compounds against HeLa, IMR-32 and MCF-7 cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. All the synthetic compounds produced a dose-dependant inhibition of growth of the cells. The IC(50) values of some compounds were comparable with standard anticancer agent, cisplatin. All the title compounds effectively scavenged the free radical, α,α-diphenyl-β-picryl hydrazyl. The test compounds having substitution with different halides (electron withdrawing groups) at C5 position showed more potent anticancer and antioxidant activities than those at C7 position. These results indicate that C5-substituted derivatives may be useful for developing antioxidant agents that play a protective role in many pathological conditions such as cancer, diabetes and so on.     

Charge Transfer-Oxy Radical Mechanism for Anticancer Agents: mAMSA Derivatives,Rhodamine 123, and Nickel Salicylaldoximate

The proposal is advanced that many anticancer agents may function via redox reactions resulting in generation of toxic oxy radicals which destroy neoplastic cells. Cyclic voltammetry was performed with some of the main types: iminium ions (protonated mAMSA derivatives), quinone derivatives (rhodamine 123) and metal complexes (nickel(II) salicylaldoximate). In addition, relevant literature data are provided. A rationale is offered that relates electrochemical data to physiological activity.     

Anticancer activity of 3-O-acyl and alkyl-(-)-epicatechin derivatives

By changing the structure or replacing the gallate group of (-)-ECG, 3-O-acyl and alkyl-(-)-epicatechin derivatives were synthesized to be screen as anticancer agents using the MTT assay in vitro against cancer cell lines (PC3, SKOV3, U373MG). 3-O-Acyl and alkyl-(-)-epicatechin derivatives (4-25) exhibited better anticancer activity than (-)-ECG and specially, compounds 6-8, 17-19, which were modified aliphatic chains with moderate sizes (C8-C12) showed strong anticancer activity (IC50=6.4-31.2 microM). The introduction of an alkyloxy group on 3-O-hydroxyl instead of an acyloxy group significantly enhanced inhibitory activity. Consequently, the compound that showed the most potency as anticancer agents were 3-O-decyl-(-)-epicatechin (18) (IC50=8.9, 7.9, 6.4 microM against PC3, SKOV3, U373MG, respectively), which modified the appropriate lipophilic group on the C-3 hydroxyl as an alkyloxy group.     

Synthesis, antiproliferative activity in cancer cells and theoretical studies of novel 6α,7β-dihydroxyvouacapan-17β-oic acid Mannich base derivatives

Natural products are great prototypes for the design of new anticancer agents. The plant-derived natural product 6α,7β-dihydroxyvouacapan-17β-oic acid (1) is promising for the development of more potent antiproliferative agents against human cancer cells. Indeed, its lactone derivative 6α-hydroxyvouacapan-7β,17β-lactone (2), a non-natural furanoditerpene, exhibited higher anticancer activity than compound 1. Herein, we describe the synthesis and antiproliferative activity of six new Mannich derivatives of compound 2 against nine cancer cell lines. Overall, our results revealed that Mannich derivatives 3-8 were more potent than compound 2 in inhibiting the proliferation of cancer cells. Theoretical studies also supported our findings, revealing the nucleophilic character of furan ring as an important feature for antiproliferative activity of the studied Mannich derivatives.     

磷光过渡金属配合物用于生物成像及癌症治疗的研究进展

顺铂及其衍生物在抗肿瘤方面取得了很大成功,但是传统的铂类抗癌药物的毒副作用和耐药性限制了这类化合物在临床上的进 一步开发。近年来,非铂类化合物,如具有 d6 电子结构的磷光过渡金属钌 ( II )、铱 ( III ) 和铼 ( I ) 配合物,由于其丰富的光物理和 光化学性质、氧化还原性质、多样的几何构型和水溶性好等优势吸引了越来越多的关注。综述上述 3 种金属配合物在生物成像及抗肿 瘤方面的研究进展。     

2-Chloro-2′-deoxyadenosine: Synthesis and Antileukemic Activity of 8-Substituted Derivatives

Abstract

A series of 8-substituted 2-chloro-2′-deoxyadenosine (2-CdA, 1) derivatives were prepared as potential anticancer agents. They were synthesized stereoselectively by the anion glycosylation of 2,6,8-trichloropurine or obtained by nucleophilic displacement reactions on 8-bromo-2-chloro-2′-deoxyadenosine (3). Within the 8-substituted CdA derivatives the 8-thioxo compound 11 was cytotoxic to several leukemia cell lines.     

New aryldithiolethione derivatives as potent histone deacetylase inhibitors

A series of dithiolethione derivatives was synthesized and the in vitro HDAC inhibitory activity was tested. The most active compounds, 1 and 2, exhibited an IC₅₀ in nM range with a strong hyperacetylation of histone H4 in A549 cells. The HDAC inhibitory activity comparable to that of SAHA and the inhibition of A549 cell proliferation suggest that these compounds are worthy of further studies as potential anticancer agents.     

Metronidazole acid acyl sulfonamide: a novel class of anticancer agents and potential EGFR tyrosine kinase inhibitors

A series of novel metronidazole derivatives were recently reported as potent anticancer agents targeting EGFR and HER-2 by our group [Qian, Y.; Zhang, H. J.; Zhang, H.; Xu, C.; Zhao, J.; Zhu, H. L. Bioorg. Med. Chem.2010, 18, 4991]. Based on the previous results, we designed and synthesized a new series of metronidazole acid acyl sulfonamide derivatives and a new series of phenylacetyl benzenesulfonamide derivatives and their anticancer activities were evaluated as potential EGFR and HER-2 kinase inhibitors. Among all the compounds, compound 12 displayed the most potent inhibitory activity EGFR and HER-2 (IC(50)=0.39 μM for EGFR and IC(50)=1.53 μM for HER-2) and it also showed the most potent growth inhibitory activity against A549 and B16-F10 cancer cell line in vitro, with an IC(50) value of 1.26 μg/mL for A549 and 0.35 μg/mL for B16-F10. Docking simulation was further performed to position compound 12 into the EGFR active site to determine the probable binding model.