Design,Synthesis, and Dual Evaluation of Quinoline and Quinolinium Iodide Salt Derivatives as Potential Anticancer and Antibacterial Agents

A series of novel quinoline and quinolinium iodide derivatives were designed and synthesized to discover potential anticancer and antibacterial agents. With regard to anticancer properties, in vitro cytotoxicities against three human cancer cell lines (A-549, HeLa and SGC-7901) were evaluated. The antibacterial properties against two strains, Escherichia coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739), along with minimum inhibitory concentration (MIC) values were evaluated. The target alkyliodine substituted compounds exhibited significant antitumor and antibacterial activity, of which compound 8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dioxolo[4,5-g]quinolin-5-ium ( 12 ) was found to be the most potent derivative with IC₅₀ values of 4.45±0.88, 4.74±0.42, 14.54±1.96, and 32.12±3.66 against A-549, HeLa, SGC-7901, and L-02 cells, respectively, stronger than the positive controls 5-FU and MTX. Furthermore, compound 12 had the most potent bacterial inhibitory activity. The MIC of this compound against both E. coli and S. aureus was 3.125 nmol ⋅ mL⁻¹, which was smaller than that against the reference agents amoxicillin and ciprofloxacin.     

吲哚酮类衍生物靶向抗肿瘤研究进展

2-吲哚酮又被称做"羟吲哚"是一种含氮的芳香杂环生物碱,许多天然化合物的结构中都含有吲哚酮结构。因其衍生物具有良好的生物活性,在靶向抗肿瘤药物领域备受关注。本文对近年来已上市的具有2-吲哚酮结构的药物和目前已报道的具有一定抗癌活性的吲哚酮类衍生物进行了综述,并对2-吲哚酮类化合物未来在靶向抗肿瘤研究领域中的发展前景进行了展望。     

Novel Triterpenic Acid—Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents

Pentacyclic triterpenes, such as betulinic, ursolic, and oleanolic acids are efficient and selective anticancer agents whose underlying mechanisms of action have been widely investigated. The introduction of N-bearing heterocycles (e.g., triazoles) into the structures of natural compounds (particularly pentacyclic triterpenes) has yielded semisynthetic derivatives with increased antiproliferative potential as opposed to unmodified starting compounds. In this work, we report the synthesis and biological assessment of benzotriazole esters of betulinic acid (BA), oleanolic acid (OA), and ursolic acid (UA) (compounds 1–3). The esters were obtained in moderate yields (28–42%). All three compounds showed dose-dependent reductions in cell viability against A375 melanoma cells and no cytotoxic effects against healthy human keratinocytes. The morphology analysis of treated cells showed characteristic apoptotic changes consisting of nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption. rtPCR analysis reinforced the proapoptotic evidence, showing a reduction in anti-apoptotic Bcl-2 expression and upregulation of the pro-apoptotic Bax. High-resolution respirometry studies showed that all three compounds were able to significantly inhibit mitochondrial function. Molecular docking showed that compounds 1–3 showed an increase in binding affinity against Bcl-2 as opposed to BA, OA, and UA and similar binding patterns compared to known Bcl-2 inhibitors.     

Kinetic Studies of Newly Patented Aminoalkanol Derivatives with Potential Anticancer Activity as Competitive Inhibitors of Prostate Acid Phosphatase

Background: Acid phosphatase and its regulation are important objects of biological and clinical research and play an important role in the development and treatment of prostate and bone diseases. The newly patented aminoalkanol (4-[2-hydroxy-3-(propan-2-ylamino)propyl]-1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione hydrochloride) (I) and (4-[3-(dimethylamino)-2-hydroxypropyl]-1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione hydrochloride) (II) derivatives have potential anticancer activity, and their influence on enzymatic activity can significantly impact the therapeutic effects of acid phosphatase against many diseases. Therefore, in this study, we investigated the action of compounds (I) and (II) on acid phosphatase. Methods: Capillary electrophoresis was used to evaluate the inhibition of acid phosphatase. Lineweaver–Burk plots were constructed to compare the Km of this enzyme in the presence of inhibitors (I) or (II) with the Km in solutions without these inhibitors. Results: Compound (I) showed a stronger competitive inhibition against acid phosphatase, whereas derivative (II) showed a weaker competitive type of inhibition. The detailed kinetic studies of these compounds showed that their type and strength of inhibition as well as affinity depend on the kind of substituent occurring in the main chemical molecule. Conclusions: This study is of great importance because the disclosed inhibition of acid phosphatase by compounds (I) and (II) raises the question of whether these compounds could have any effect on the treatment possibilities of prostate diseases.     

Recent Advances in the Discovery of Multitargeted Tyrosine Kinase Inhibitors as Anticancer Agents

The treatment of cancer has been one of the most significant challenges for the medical field. Further research on the signal transduction pathway of tumor cells is driving the rapid development of antitumor agents targeting tyrosine kinases. However, most of the currently approved tyrosine kinase inhibitors based on the “single target/single drug” design are becoming less and less effective in the treatment of complex, heterogeneous, and multigenic cancers; this also results in resistance to chemotherapy. In contrast, multitargeted tyrosine kinase inhibitors (MT-TKIs) can effectively block multiple pathways of intracellular signal transduction. Therefore, they have therapeutic advantages over single-targeted inhibitors and have become a hotspot in antitumor drug research in recent years. This minireview summarizes recent advances in the discovery of MT-TKIs based on their chemical structures. In particular, we describe the kinase inhibitory and antitumor activity of promising compounds, as well as their structure – activity relationships (SARs).     

Polypyridyl CoII-Curcumin Complexes as Photoactivated Anticancer and Antibacterial Agents

Four new Co^II complexes, [Co(bpy)₂(acac)]Cl ( 1 ), [Co(phen)₂(acac)]Cl ( 2 ), [Co(bpy)₂(cur)]Cl ( 3 ), [Co(phen)₂(cur)]Cl ( 4 ), where bpy=2,2’-bipyridine ( 1 and 3 ), phen=1,10-phenanthroline ( 2 and 4 ), acac = acetylacetonate ( 1 and 2 ), cur=curcumin monoanion ( 3 and 4 ) have been designed, synthesized and fully characterized. The X-ray crystal structures of 1 and 2 indicated that the CoN₄O₂ core has a distorted octahedral geometry. The photoactivity of these complexes was tuned by varying the π conjugation in the ligands. Curcumin complexes 3 and 4 had an intense absorption band near 435 nm, which made them useful as visible-light photodynamic therapy agents; they also showed fluorescence with λ_em≈565 nm. This fluorescence was useful for studying their intracellular uptake and localization in MCF-7 breast cancer cells. The acetylacetonate complexes ( 1 and 2 ) were used as control complexes to understand the role of curcumin. The white-light-triggered anticancer profiles of the cytosol targeting complexes 3 and 4 were investigated in detail. These non-dark toxic complexes displayed significant apoptotic photo-cytotoxicity (under visible light) against MCF-7 cells through ROS generation. The control complexes 1 and 2 did not induce significant cell death in the light or dark. Interestingly, 1-4 produced a remarkable antibacterial response upon light exposure. Overall, the reported results here can increase the boundary of the Co^II-based anticancer and antibacterial drug development.     

Novel Pyrimidine Derivatives as Potential Anticancer Agents: Synthesis,Biological Evaluation and Molecular Docking Study

In the present paper, new pyrimidine derivatives were designed, synthesized and analyzed in terms of their anticancer properties. The tested compounds were evaluated in vitro for their antitumor activity. The cytotoxic effect on normal human dermal fibroblasts (NHDF) was also determined. According to the results, all the tested compounds exhibited inhibitory activity on the proliferation of all lines of cancer cells (colon adenocarcinoma (LoVo), resistant colon adenocarcinoma (LoVo/DX), breast cancer (MCF-7), lung cancer (A549), cervical cancer (HeLa), human leukemic lymphoblasts (CCRF-CEM) and human monocytic (THP-1)). In particular, their feature stronger influence on the activity of P-glycoprotein of cell cultures resistant to doxorubicin than doxorubicin. Tested compounds have more lipophilic character than doxorubicin, which determines their affinity for the molecular target and passive transport through biological membranes. Moreover, the inhibitory potential against topoisomerase II and DNA intercalating properties of synthesized compounds were analyzed via molecular docking.     

Tubulin Photoaffinity Labeling with Biotin‐Tagged Derivatives of Potent Diketopiperazine Antimicrotubule Agents

NPI‐2358 ( 1 ) is a potent antimicrotubule agent that was developed from a natural diketopiperazine, phenylahistin, which is currently in Phase I clinical trials as an anticancer drug. To understand the precise recognition mechanism of tubulin by this agent, we focused on its potent derivative, KPU‐244 ( 2 ), which has been modified with a photoreactive benzophenone structure, and biotin‐tagged KPU‐244 derivatives ( 3 and 4 ), which were designed and synthesized for tubulin photoaffinity labeling. Introduction of the biotin structure at the p′‐position of the benzophenone ring in 2 exhibited reduced, but significant biological activities with tubulin binding, tubulin depolymerization and cytotoxicity in comparison to the parent KPU‐244. Therefore, tubulin photoaffinity labeling studies of biotin‐derivatives 3 and 4 were performed by using Western blotting analysis after photoirradiation with 365 nm UV light. The results indicated that tubulin was covalently labeled by these biotin‐tagged photoprobes. The labeling of compound 4 was competitively inhibited by the addition of diketopiperazine 1 or colchicine, and weakly inhibited by the addition of vinblastine. The results suggest that photoaffinity probe 4 specifically recognizes tubulin at the same binding site as anticancer drug candidate 1 , and this leads to the disruption of microtubules. Probe 4 serves well as a useful chemical probe for potent antimicrotubule diketopiperazines, much like phenylahistin, and it also competes for the colchicine‐binding site.     

Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium tuberculosis

Tuberculosis (TB) is currently the leading cause of death related to infectious diseases worldwide, as reported by the World Health Organization. Moreover, the increasing number of multidrug-resistant tuberculosis (MDR-TB) cases has alarmed health agencies, warranting extensive efforts to discover novel drugs that are effective and also safe. In this study, 23 new compounds were synthesized and evaluated in vitro against the drug-resistant strains of M. tuberculosis. The compound 6-((3-fluoro-4-thiomorpholinophenyl)carbamoyl)benzo[c][1,2,5]oxadiazole 1-N-oxide ( 5 b ) was particularly remarkable in this regard as it demonstrated MIC₉₀ values below 0.28 μM against all the MDR strains evaluated, thus suggesting that this compound might have a different mechanism of action. Benzofuroxans are an attractive new class of anti-TB agents, exemplified by compound 5 b , with excellent potency against the replicating and drug-resistant strains of M. tuberculosis.     

A Synthetic Overview of Benzoxazines and Benzoxazepines as Anticancer Agents

Benzoxazines and benzoxazepines are nitrogen and oxygen-containing six and seven-membered benzo-fused heterocyclic scaffolds, respectively. Benzoxazepines and benzoxazines are well-known pharmacophores in pharmaceutical chemistry, which are of significant interest and have been extensively studied because of their promising activity against various diseases including their wide range of anticancer activity. Several reports are known for synthesizing benzoxazine and benzoxazepine-based compounds in the literature. Herein this review provides a critical analysis of synthetic strategies towards benzoxazines and benzoxazepines along with various ranges of anticancer activities based on these molecules that have been reported from 2010 onwards. This review also focuses on the structure-activity relationship of the benzoxazine and benzoxazepine scaffolds containing bioactive compounds and describes how the structural modification affects their anticancer activity.     

Synthesis of Potential Pharmaceutical Heterocycles as Surface Active Agents

Isoxazole, pyrazole, pyran, pyridine and pyrimidine derivatives of fatty acids were synthesized as surface and bioactive heterocycles. Hydroxylation of these intermediates by propylene oxide produced easy‐to‐handle, efficient and quickly biodegradable surface active agents, which revealed the importance of their applications in safety for humans as well as the environment. These compounds showed good activity against bacteria and fungi, showing promise in applications of drugs, cosmetics, and pesticides.     

2-Hydroxy-4-benzyloxylimine Resveratrol Derivatives as Potential Multifunctional Agents for the Treatment of Parkinson's Disease

A series of 2-hydroxy-4-benzyloxylimine resveratrol derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of Parkinson's disease. The results revealed that most derivatives possessed good multifunctional activities. Among them, representative compound (E)-5-[(4-fluorobenzyl)oxy]-2-{[(4-hydroxyphenyl)imino]methyl}phenol ( 7 h ) exhibited excellent MAO-B inhibition (IC₅₀=8.43×10⁻³ μM) and high antioxidant activity (ORAC=3.45 Trolox equivalent). Additionally, 7 h displayed good metal chelating ability, appropriate blood–brain barrier (BBB) permeability, significant neuroprotective effect, and great anti-neuroinflammatory activity. Furthermore, 7 h can also ameliorate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease symptoms in mice. Therefore, compound 7 h was found to be a promising candidate for further development against PD.     

Selected Monocyclic Monoterpenes and Their Derivatives as Effective Anticancer Therapeutic Agents

Terpenes—a diverse group of secondary metabolites—constitute the largest class of natural products abundant in almost every plant species. The properties of concrete terpenes and essential oils have been intensively studied due to their widespread use in the pharmaceutical, food and cosmetics industries. Despite the popularity of these aromatic compounds, their derivatives, terpenoids, are still not comprehensively characterized despite exhibiting potent bioactive properties. This review aims to assess the anticancer properties of selected monoterpenes including carvone, carvacrol, perillyl alcohol, perillaldehyde, limonene, menthol and their derivatives while also evaluating potential applications as novel anticancer treatments. Special attention is paid to functional groups that improve the bioactivity of monoterpene molecules. This review also covers the therapeutic potential of deep eutectic solvents that contain monoterpene substances. Taken together, the literature supports the use of monoterpene derivatives in the development of new alternatives for disease treatment and prevention.     

Design,Synthesis, and Biological Evaluation of Shikonin and Alkannin Derivatives as Potential Anticancer Agents via a Prodrug Approach

To minimize the cytotoxicity of shikonin and alkannin that arises through the generation of reactive oxygen species (ROS) and alkylation of the naphthazarin ring, two series of novel core‐scaffold‐modified shikonin and alkannin derivatives were designed. These derivatives, which differ in their configurational and positional isomerism (R‐, S‐, and 2‐ and 6‐isomers) were synthesized in high enantiomeric excess (>99 % ee). The selectivity of the dimethylated derivatives was significantly higher than the parent shikonin in vitro, but some side effects were still observed in vivo. Surprisingly, the dimethylated diacetyl derivatives with poor anticancer activity in vitro showed tumor‐inhibiting effects similar to paclitaxel without any toxicity in vivo. The anticancer activity of these derivatives is in agreement with their low ROS generation and alkylating capacity, emphasizing their potential as prodrugs. This strategy provides means to address the nonspecific cytotoxicity of naphthazarin analogues toward normal cells.     

Catalase Inhibition by Aminoalkanol Derivatives with Potential Anti-Cancer Activity—In Vitro and In Silico Studies Using Capillary Electrophoresis Method

In this work, the investigation of type and inhibitory strength of catalase by two pairs of aminoalkanol derivatives (1,7 diEthyl- and 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene- 3,5,10-trione) has been presented. The obtained results allowed for the determination of all kinetic parameters (Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC₅₀) on the basis of which it was shown that all four aminoalkanol derivatives are competitive inhibitors of catalase. However, the strength of action of each of them depends on the type of substituents present in the main structure of the molecule. Subtle differences in the potency of individual derivatives were possible to detect thanks to the developed, sensitive method of capillary electrophoresis, which allowed simultaneous monitoring of the mutual changes in the concentrations of substrates and products of the reaction catalyzed by the enzyme. Detailed values of kinetic parameters showed that all derivatives are weak inhibitors of catalase, which in this case is a big advantage because each inhibition of catalase activity is associated with a greater amount of accumulated, harmful reactive oxygen species. The results of docking studies also show the convergence of the binding energies values of individual inhibitors with all kinetic parameters of the investigated catalase inhibition and thus additionally confirm the weak inhibitory strength of all four aminoalkanol derivatives.     

Design,Synthesis and Biological Evaluation of Steroidal Glycoconjugates as Potential Antiproliferative Agents

To systematically evaluate the impact of neoglycosylation upon the anticancer activities and selectivity of steroids, four series of neoglycosides of diosgenin, pregnenolone, dehydroepiandrosterone and estrone were designed and synthesized according to the neoglycosylation approach. The structures of all the products were elucidated by NMR analysis, and the stereochemistry of C20-MeON-pregnenolone was confirmed by crystal X-ray diffraction. The compounds′ cytotoxicity on five human cancer cell lines was evaluated using a Cell Counting Kit-8 assay, and structure–activity relationships (SAR) are discussed. 2-deoxy-d -glucoside 5 k displayed the most potent antiproliferative activities against HepG2 cells with an IC₅₀ value of 1.5 μM. Further pharmacological experiments on compound 5 k on HepG2 cells revealed that it could cause morphological changes and cell-cycle arrest at the G0/G1 phase and then induced the apoptosis, which might be associated with the enhanced expression of high-mobility group Box 1 (HMGB1). Taken together, these findings prove that the neoglycosylation of steroids could be a promising strategy for the discovery of potential antiproliferative agents.     

Identification of KPNB1 as a Cellular Target of Aminothiazole Derivatives with Anticancer Activity

We found that aminothiazole derivative (E)‐N‐(5‐benzylthiazol‐2‐yl)‐3‐(furan‐2‐yl)acrylamide ( 1 ) has strong anticancer activity, and undertook proteomics approaches to identify the target protein of compound 1 , importin β1 (KPNB1). A competitive binding assay using fluorescein‐labeled 1 showed that 1 has strong binding affinity for KPNB1 (K_d: ～20 nm ). Furthermore, through western blotting assays for KPNB1, KPNA2, EGFR, ErbB2, and STAT3, we confirmed that 1 has inhibitory effects on the importin pathway. KPBN1 appears to be overexpressed in several cancer cells, and siRNA‐induced inhibition of KPNB1 shows significant inhibition of cancer cell proliferation, while leaving non‐cancerous cells unaffected. Therefore, compound 1 is a promising new lead for the development of KPNB1‐targeted anticancer agents. Fluorescein‐labeled 1 could be a useful quantitative probe for the development of novel KPNB1 inhibitors.     

sp3-Rich Glycyrrhetinic Acid Analogues Using Late-Stage Functionalization as Potential Breast Tumor Regressing Agents

Late-stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C−H bonds on pre-existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A-ring, expanding the A-ring and selectively activating one methyl group of the gem-dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA-MB-231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproliferative and anti-invasive effects through enhanced mitochondrial superoxide production with parallel depletion of GSH levels. Furthermore, intraperitoneal administration of these two compounds, in comparison with GA, greatly regressed breast tumor growth and metastasis in a SCID mouse model bearing labeled MDA-MB-231 cells.     

新型甲硝唑-苯腙类化合物的设计、合成及抗菌活性研究

以甲硝唑、对羟基苯甲醛及取代肼为原料,经过3步反应,以较高产率合成得到一类新型的甲硝唑-苯腙类化合物,其结构经~1HNMR、~(13)CNMR和元素分析确证,所得化合物经抗菌活性筛选研究。结果表明,大部分化合物都具有较强的抗菌活性。其中以(E)-4-(2-(4-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)肼基)苯磺酰胺活性最好,对大肠杆菌、铜绿假单胞菌、金黄色葡萄球菌和枯草芽孢杆菌的最低抑制浓度分别为1.56、0.78、0.39和0.39μg/m L。