Synthesis and biological evaluation of new mono naphthalimide platinum(IV) derivatives as antitumor agents with dual DNA damage mechanism

Naphthalimide has emerged as an interesting DNA intercalator and possessed attracting antitumor properties. In this context, naphthalimide group was linked to platinum(IV) core to construct a series of new mono naphthalimide platinum(IV) derivatives. The title compounds exert effective antitumor activities to the tested tumor cells lines in vitro, especially the one with propionyl chain displays comparable or even better bioactivities than platinum(II) reference drugs cisplatin and oxaliplatin. Moreover, the mono naphthalimide platinum(IV) derivative displays comparable tumor growth inhibitory competence against CT26 xenograft tumors in BALB/c mice in vivo without severe toxic effects in contrast to oxaliplatin. A dual DNA damage mechanism was proven for the title complex. Both naphthalimide ligand and the liberated platinum(II) moiety could generate DNA lesions to tumor cells synergistically and active the apoptotic pathway by up-regulating the expression of caspase 9 and caspase 3. Meanwhile, the conversion of platinum(II) drug into tetravalent form by incorporating naphthalimide moiety increases the uptake of platinum in whole cells and DNA remarkably. All these facts might be the factors for the title platinum(IV) complexes to overcome platinum(II) drug resistance. Additionally, the mono naphthalimide platinum(IV) complex could interact with human serum albumin by hydrogen bond and van der Waals force which would further influence their storage, transport and bioactivities.     

1,8‐Naphthalimide: A Potent DNA Intercalator and Target for Cancer Therapy

The poor pharmacokinetics, side effects and particularly the rapid emergence of drug resistance compromise the efficiency of clinically used anticancer drugs. Therefore, the discovery of novel and effective drugs is still an extremely primary mission. Naphthalimide family is one of the highly active anticancer drug based upon effective intercalator with DNA. In this article, we review the discovery and development of 1,8‐naphthalimide moiety, and, especially, pay much attention to the structural modifications and structure activity relationships. The review demonstrates how modulation of the moiety affecting naphthalimide compound for DNA binding that is achieved to afford a profile of antitumor activity. The DNA binding of imide and ring substitution at naphthalimide, bisnaphthalimide, naphthalimide‐metal complexes is achieved by molecular recognition through intercalation mode. Thus, this synthetic/natural small molecule can act as a drug when activation or inhibition of DNA function, is required to cure or control the cancer disease. The present study is a review of the advances in 1,8‐naphthalimide‐related research, with a focus on how such derivatives are intercalated into DNA for their anticancer activities.     

Sequence-dependent interactions of cationic naphthalimides and polynucleotides

The binding interactions of three naphthalimide derivatives with heteropoly nucleic acids have been evaluated using fluorescence, absorption and circular dichroism spectroscopies. Mono- and bifunctionalized naphthalimides exhibit sequence-dependent variations in their affinity toward DNA. The heteropoly nucleic acids, [Poly(dA-dT)]2 and [Poly(dG-dC)]2, as well as calf thymus (CT) DNA, were used to understand the factors that govern binding strength and selectivity. Sequence selectivity was addressed by determining the binding constants as a function of polynucleotide composition according to the noncooperative McGhee-von Hippel binding model. Binding affinities toward [poly(dA-dT)](2) were the largest for spermine-substituted naphthalimides (Kb = 2-6 x 10(6) M(-1)). The association constants for complex formation between the cationic naphthalimides and [poly(dG-dC)]2 or CT DNA (58% A-T content) were 2-500 times smaller, depending on the naphthalimide-polynucleotide pair. The binding modes were also assessed using a combination of induced circular dichroism and salt effects to determine whether the naphthalimides associate with DNA through intercalative, electrostatic or groove-binding. The results show that the monofunctionalized spermine and pyridinium-substituted naphthalimides associate with DNA through electrostatic interactions. In contrast, intercalative interactions are predominant in the complex formed between the bifunctionalized spermine compound and all of the polynucleotides.     

咪唑修饰萘酰亚胺与DNA的作用及其细胞毒性

设计合成了咪唑及其烷基化咪唑阳离子基团修饰的萘酰亚胺衍生物。利用紫外-可见吸收光谱、荧光光谱、圆二色谱和荧光共振能量转移等方法研究了它们与小牛胸腺DNA(CT DNA)和G-四链体DNA的相互作用。这些化合物对端粒DNA序列的G-四链体有很高的结合能力(K_α4×10~6 L·mol~(-1)),并能够稳定G-四链体。DNA粘度实验结果表明萘酰亚胺衍生物与CT DNA通过插入作用结合。Autodock分子对接模拟结果表明这些化合物通过疏水作用、静电作用或氢键等方式与人体端粒G-四链体的loop和沟槽部分结合。咪唑阳离子基团修饰的萘酰亚胺衍生物4a–c能够定位于细胞核,对肺癌细胞的细胞毒性要高于咪唑基团修饰的萘酰亚胺衍生物3。化合物4a和4b对肺癌细胞A549的细胞毒性明显高于正常人胚肺成纤维细胞MRC-5,表现出良好的抗癌活性。     

Identification of Novel 4′-O-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II

C4 variation of 4′-O-demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substituents. Notably, most compounds showed significant inhibition against the etoposide (2)-resistant KBvin cells. Four of the compounds (11, 18, 27 and 28) induced protein-linked DNA break (PLDB) levels higher than those of GL-331 (6) and 2, and are assumed to be topoisomerase II (topo II) poisons more potent than 6 and 2. Compound 28, a potent topo II poison highly effective against KBvin cells, was further evaluated with a panel of tumor cells and was most active against HepG2. This compound also exhibited apparent in vivo antitumor efficacy in hepatoma 22 (H22) mouse model. The results indicated that C4 derivation of DMEP is a feasible approach to identify potent topo II inhibitors with optimized antitumor profiles.     

Synthesis of thiazo- or thiadiazo- naphthalene carboxamides via mercuric intermediates and their antitumor and DNA photocleavage activities

Two kinds of thiazo- or thiadiazo- naphthalene carboxamides with aminoalkyl side chains at 5- or 6-position modified from naphthalimides were designed, synthesized and quantitatively evaluated as antitumor and DNA photocleaving agents. The compound with aminoalkyl side chain at 6-position showed stronger antitumor (A549, P388) and DNA photocleaving abilities than its isomer with that at 5-position. B₂, the most efficient DNA photocleaver, also exhibited the highest cytotoxicity with the IC₅₀ of 2.53 and 0.11 μM against cell lines of A549 and P388, respectively. These compounds also photocleaved DNA more efficiently than their corresponding naphthalimides.     

Targeting DNA Topoisomerase II in Antifungal Chemotherapy

Topoisomerase inhibitors have been in use clinically for the treatment of several diseases for decades. Although those enzymes are significant molecular targets in antibacterial and anticancer chemotherapy very little is known about the possibilities to target fungal topoisomerase II (topo II). Raising concern for the fungal infections, lack of effective drugs and a phenomenon of multidrug resistance underlie a strong need to expand the range of therapeutic options. In this review paper, we discussed the usefulness of fungal topo II as a molecular target for new drug discovery. On the basis of previously published data, we described structural and biochemical differences between fungal and human enzymes as well as a molecular basis of differential sensitivity to known anticancer drugs targeting the latter. This review focuses especially on highlighting the differences that may underlie the selectivity of action of new inhibitors. Distinct sites within fungal topo II in comparison with human counterparts are observed and should be further studied to understand the significance of those sites and their possible usage in design of new drugs.     

New Cisplatin Analogues—On the Way to Better Antitumor Agents

The clinical success of cisplatin (cis -diamminedichloroplatinum(II )) in antitumor chemotherapy has encouraged an all-out search for analogues with lower toxicity, improved therapeutic index and increased activity. Literally thousands of analogues, obtained by replacement of the ammine- and chloro-ligands by other amines and anionic ligands, respectively, have been systematically screened for activity in experimental tumor models. Some of these analogues have been selected for clinical evaluation, but only very few of them appear to be promising antitumor agents. More recently, cisplatin analogues have been designed and synthesized on the basis of, inter alia, the following considerations: 1) platinum complexes with carrier molecules as ligands should prove useful for achieving increasing drug concentration in tumor tissues; 2) platinum complexes with chemotherapeutic agents as ligands could afford polyfunctional drugs with synergistic action; 3) complexes containing more than one platinum atom might be more effective than complexes containing only one platinum atom; 4) platinum complexes could be used as sensitizers in radiation therapy. In this paper, we shall give a brief account of the “traditional” analogues, and then critically discuss what we believe could be the new trends in the design of cisplatin analogues.     

Novel seven-membered ring-fused naphthalimide derivatives with potentials for cancer theranostics

Naphthalimide derivatives have good planarity and large conjugated structure and therefore possess photophysical properties and biological activities. Previously, our group discovered seven-membered heterocyclic derivatives via modifying 4- and 5-positions of naphthalimide skeleton and found the derivatives had good water solubility and showed large stokes shift and strong fluorescence in water. In this article, we designed and synthesized more seven-membered ring-fused naphthalimide derivatives (Y1-Y16) by introducing different substitutions on the imide group. Among them, Y1, Y5, Y9 were found to show similar cytotoxic activities with Amonafide against A549 and HL60 cells, with IC₅₀ values at 10^?6 mol/L. What is more, the asymmetry derivatives (Y1 and Y5) showed high fluorescent quantum yields in the aqueous phase (Ф = 0.47). Considering the great fluorescence quantum yields in water and the potent anti-tumor activities of the representative seven-membered ring-fused naphthalimides, they have potentials to be used as agents for cancer theranostics.     

Revisiting Phosphorus Analogues of Phthalimides and Naphthalimides: Syntheses and Comparative Studies

A series of phosphorus analogues of aromatic‐fused monoimides (phthalimides and naphthalimides) bearing a mesityl group on the P center have been synthesized. In a comparison of their photophysical, electrochemical, and thermal properties with those of the corresponding imides, the impact of P incorporation was revealed. Furthermore, theoretical studies using DFT methods were conducted to understand their properties.     

Biosynthesis of DNA-Alkylating Antitumor Natural Products

DNA-alkylating natural products play an important role in drug development due to their significant antitumor activities. They usually show high affinity with DNA through different mechanisms with the aid of their unique scaffold and highly active functional groups. Therefore, the biosynthesis of these natural products has been extensively studied, especially the construction of their pharmacophores. Meanwhile, their producing strains have evolved corresponding self-resistance strategies to protect themselves. To further promote the functional characterization of their biosynthetic pathways and lay the foundation for the discovery and rational design of DNA alkylating agents, we summarize herein the progress of research into DNA-alkylating antitumor natural products, including their biosynthesis, modes of action, and auto-resistance mechanisms.     

萘酰亚胺多胺衍生物的合成及其抗肿瘤活性

设计合成了萘酰亚胺的4种新的多胺衍生物并进行了体外抗肿瘤活性测试。结果表明,这些萘酰亚胺衍生物能够嵌入DNA碱基对中,并且比氨萘非特对肿瘤细胞具有更高的毒性和更好的选择性,其中化合物3b对4种肿瘤细胞的抑制IC50值分别为7.80、5.08、9.78和9.27μmol/L;高内涵活细胞成像系统结果显示,这些化合物可能是通过线粒体通路而导致的细胞凋亡。     

Naphthalimide‐Based Triptycenes: Synthesis and Optoelectronic Properties

In the past decades, the naphthalimide structure has found application in many areas of chemistry due to its unique photophysical properties. Naphthalimide has two isomers, 1,8‐naphthalimide containing a six‐membered imide ring and 2,3‐naphthalimide containing a five‐membered imide ring. The former has been widely investigated while studies on the latter are considerably more rare. On the other hand, naphthalimide can also be regarded as a building block to construct polycyclic aromatic hydrocarbons (PAHs), which have found wide applications in optical materials. Here we report the synthesis and optoelectronic properties of three 2,3‐naphthalimide‐based triptycenes. These three triptycene derivatives enrich the family of triptycenes.     

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.     

Evaluation of inhibitory effects of benzothiazole and 3-amino-benzothiazolium derivatives on DNA topoisomerase II by molecular modeling studies

There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies.     

Semiempirical study on the electronic structure of antitumor drugs ellipticines, olivacines and isoellipticines

Ellipticine [5,11-dimethyl-6H-pyrido[4,3]carbazole] is a planar organic compound isolated from the plant extract of Ochrosia elliptica, with a high degree of antitumor and cytotoxic activity. Ellipticine and its derivatives have different modes of action, which may include intercalation or covalent binding to DNA and interference with the activity of topoisomerase II. In the present work we studied the electronic, geometrical and spectroscopic properties of 31 ellipticine derivatives and analogue compounds, using the semiempirical methods Parametric Method 3 and Zerner's Intermediate Neglect of Differential Overlap. The Zero Differential Overlap semiempirical Molecular Electrostatic Potential (MEP) was also calculated in order to interpret the electronic structure of the molecules. For the biologically tested ellipticines and olivacines we have observed a rule based on the dipole moment values and a selective distribution of active sites (coming from the MEP calculations) that can be used to identify the active molecules. These results provide a pattern which can be used to select potentially active molecules from the untested group of molecules and to design new ellipticine derivatives with improved antitumor activity.     

Hoechst-naphthalimide dyad with dual emissions as specific and ratiometric sensor for nucleus DNA damage

A ratiometric fluorescent sensor (Hoe-NI) was developed for high specific nucleus labeling and monitoring of nuclear DNA damage in living cells.     

New Synthesis of Pyrazolo[3,4‐b][1,4,5]benzothiadiazepine, ‐[1,4,5]benzoxadiazepine, ‐[1,4,5]benzotriazepine and Pyrazolo[3,4‐b]quinoxaline Derivatives

New pyrazolo[3,4‐b][1,4,5]benzothiadiazepine and its analogues 3 have been obtained by reaction of 4‐nitrosopyrazoles 1 with 2‐aminothiophenol 2a and its analogues 2b,c . Under fused conditions, dipyrazolyl derivatives 7a was obtained with a trace amount of quinoxaline 5a . On the other hand, 5b and 7b were obtained in equal amounts. A proposed pathway is presented.     

FORMATION OF THIADIAZOLE AND THIAZOLE RINGS FROM HETEROCYCLES WITH A THIOAMIDE SIDE CHAIN

Abstract

Substituted or unsubstituted thioureido heterocycles can be successfully used for the formation of a new thiadiazole or thiazole ring. For example, a fused thiadiazolo ring is formed either from carbethoxythioureido- or carbethoxymethylthioureido-heterocycles (I). The reaction proceeds by oxidative cyclization and can be performed in the presence of various oxidizing agents. On the other hand, some reducing agents convert II back into I. A particular case represents the reaction between 2-chloro-3-aminopyridine and carbethoxy isothiocyanate giving directly III (R = = COOEt), although the reaction must proceed via an intermediate like I (n = O).     

Dual Topoisomerase I/II Inhibition-Induced Apoptosis and Necro-Apoptosis in Cancer Cells by a Novel Ciprofloxacin Derivative via RIPK1/RIPK3/MLKL Activation

Fluoroquinolones (FQs) are synthetic broad-spectrum antimicrobial agents that have been recently repurposed to anticancer candidates. Designing new derivatives of FQs with different moieties to target DNA topoisomerases could improve their anticancer efficacy. The present study aimed to synthesize a novel ciprofloxacin derivative, examine its anticancer activity against HepG2 and A549 cancer cells, and investigate the possible molecular mechanism underlying this activity by examining its ability to inhibit the topo I/II activity and to induce the apoptotic and necro-apoptotic pathways. Molecular docking, cell viability, cell migration, colony formation, cell cycle, Annexin V, lactate dehydrogenase (LDH) release, ELISA, and western blotting assays were utilized. Molecular docking results showed that this novel ciprofloxacin derivative exerted dual topo I and topo II binding and inhibition. It significantly inhibited the proliferation of A549 and HepG2 cancer cells and decreased their cell migration and colony formation abilities. In addition, it significantly increased the % of apoptotic cells, caused cell cycle arrest at G2/M phase, and elevated the LDH release levels in both cancer cells. Furthermore, it increased the expression of cleaved caspase 3, RIPK1, RIPK3, and MLKL proteins. This novel ciprofloxacin derivative exerted substantial dual inhibition of topo I/II enzyme activities, showed antiproliferative activity, suppressed the cell migration and colony formation abilities for A549 and HepG2 cancer cells and activated the apoptotic pathway. In addition, it initiated another backup deadly pathway, necro-apoptosis, through the activation of the RIPK1/RIPK3/MLKL pathway.