Design,Synthesis, and Molecular Docking of Paracyclophanyl-Thiazole Hybrids as Novel CDK1 Inhibitors and Apoptosis Inducing Anti-Melanoma Agents

Three new series of paracyclophanyl-dihydronaphtho[2,3-d]thiazoles and paracyclophanyl-thiazolium bromides were designed, synthesized, and characterized by their spectroscopic data, along with X-ray analysis. One-dose assay results of anticancer activity indicated that 3a–e had the highest ability to inhibit the proliferation of different cancer cell lines. Moreover, the hybrids 3c–e were selected for five-dose analyses to demonstrate a broad spectrum of antitumor activity without apparent selectivity. Interestingly, series I compounds (Z)-N-substituted-4,9-dihydronaphtho[2,3-d]thiazol-3(2H)-yl)-4′-[2.2]paracyclophanylamide) that are carrying 1,4-dihydronaphthoquinone were more active as antiproliferative agents than their naphthalene-containing congeners (series II: substituted 2-(4′-[2.2]paracyclophanyl)hydrazinyl)-4-(naphth-2-yl)-thiazol-3-ium bromide hybrids) and (series III: 3-(4′-[2.2]paracyclophanyl)amido-2-(cyclopropylamino)-4-(naphth-2-yl)thiazol-3-ium bromide) toward the SK-MEL-5 melanoma cell line. Further antiproliferation investigations of 3c and 3e on the healthy, normal unaffected SK-MEL-5 cell line indicated their relative safety. Compound 3c showed an inhibition of eight isoforms of cyclin-dependent kinases (CDK); however, it exhibited the lowest IC₅₀ of 54.8 nM on CDK1 in comparison to Dinaciclib as a reference. Additionally, compound 3c revealed a remarkable downregulation of phospho-Tyr15 with a level (7.45 pg/mL) close to the reference. 3c mainly showed cell cycle arrest in the pre-G1 and G2/M phases upon analysis of the SK-MEL-5 cell line. The sequential caspase-3 assay for 3c indicated a remarkable overexpression level. Finally, a molecular docking study was adopted to elucidate the binding mode and interactions of the target compounds with CDK1.     

Potent Dual BET/HDAC Inhibitors for Efficient Treatment of Pancreatic Cancer

As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small‐molecule inhibitors that simultaneously target bromodomain and extra‐terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor ( 13 a ) is identified to possess excellent and balanced activities against BRD4 BD1 (IC₅₀=11 nm ) and HDAC1 (IC₅₀=21 nm ). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)‐JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer.     

Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo

Monosaccharides are added to the hydrophilic face of a self‐assembled asymmetric Fe^II metallohelix, using CuAAC chemistry. The sixteen resulting architectures are water‐stable and optically pure, and exhibit improved antiproliferative selectivity against colon cancer cells (HCT116 p53^+/+) with respect to the non‐cancerous ARPE‐19 cell line. While the most selective compound is a glucose‐appended enantiomer, its cellular entry is not mainly glucose transporter‐mediated. Glucose conjugation nevertheless increases nuclear delivery ca 2.5‐fold, and a non‐destructive interaction with DNA is indicated. Addition of the glucose units affects the binding orientation of the metallohelix to naked DNA, but does not substantially alter the overall affinity. In a mouse model, the glucose conjugated compound was far better tolerated, and tumour growth delays for the parent compound (2.6 d) were improved to 4.3 d; performance as good as cisplatin but with the advantage of no weight loss in the subjects.     

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.     

Theoretical Investigation of Detailed Thermodynamic Character of Possible Difunctional Adducts Model

1 INTRODUCTION Since cisplatin was recognized as an active sub- stance in the antitumor treatment in 1960s, many studies have been devoted to the exploitation of pla- tinum complexes, focusing on the influence of dif- ferent ligands and conformers on the cancer acti- vity[1~7]. Thousands of Pt complexes evaluated for antitumor activity adhered to the set of structure- activity relationship summarized by Cleare and Ho- eschele[1, 8], for instance, cispaltin, carboplatin and oxaliplatin pos…     

α-取代氨基氟代苯基膦酸酯衍生物的合成、晶体结构与抗癌活性

利用席夫碱与亚磷酸酯反应, 合成了新型O,O'-二烷基-α-(6-甲氧苯并噻唑-2-基氨基)-4-氟苯基膦酸酯化合物, 结构经元素分析, IR, ¹H NMR, ¹³C NMR和X单晶衍射确认. X单晶衍射测试结果表明: 化合物3d分子属于四面体晶系, 空间群I4(1)/a, a＝2.1055(3) nm, b＝2.1055(3) nm, c＝2.0521(5) nm, α＝90.00°, β＝90.00°, γ＝90.00°, V＝0.9098(3) nm³, Z＝16, D_c＝1.321 mg/m³, ＝0.250 mm^－1, F(000)＝3808. 化合物还存在着1个分子内氢键[N(2)—H(2)…O(1)]. 生物测定表明化合物3f在20 g/mL浓度下对PC3细胞的抑制率为84.3%.     

4(3H)-喹唑啉酮芳胺衍生物的合成及其抗肿瘤活性评价

根据非经典抗叶酸剂的结构特点,将抗肿瘤药效团三甲氧基苯基与4(3H)-喹唑啉酮结构相结合,设计了一系列具有芳胺侧链的4(3H)-喹唑啉酮衍生物。使用适量的卤代烷,在室温下对3．4,5-三甲氧基苯胺进行N-烷基化反应,制得了4种N-取代的3,4,5-三甲氧基苯胺,收率为30．3％～60．6％。将2-甲基-6-溴甲基-4(3H)-喹唑啉酮与3,4,5-三甲氧基苯胺、N-取代的3,4．5-三甲氧基苯胺以及其它芳胺在室温下反应,以30．8％～71．9％的收率合成了目标化合物8a～8m,其结构用ESI-MS、~1H NMR、元素分析或HRMS测试技术进行了表征。采用MTF法测试了化合物8a～8m对人非小细胞肺癌A-549、结肠癌HCT-8和肝癌Bel-7402细胞的体外抗肿瘤活性。结果表明,在5×10~(-6)g/mL质量浓度下所合成的化合物对3种肿瘤细胞的体外生长的抑制率均低于25％。     

由藜芦醛合成娃儿藤碱

以藜芦醛(1)、3,4-二甲氧基苯乙酸(2)、(S)-L-脯氨酸(6)等为原料,经8步反应,合成了一种抗肿瘤活性(s)-( )-娃儿藤碱。先由化合物1和2在乙酸酐/三乙胺催化下反应得到3,4-二甲氧基一反式-α-(3′, 4′-二甲氧基苯基)．肉桂酸(3),在0℃、三氟乙酸存在下用VOF_3对其关环成2,3,6,7-四甲氧基-9-羧基菲(4),然后用喹啉作介质,在230℃、无水CuSO_4催化下脱去羧基,得到2,3,6,7-四甲氧基菲(5),再和(S)-N- (三氟乙酰)-L-脯氨酰氯(6b)傅-克反应得到(S)-N-(三氟乙酰基)-2,3,6,7-四甲氧基-9-L-脯氨酰基菲(7),并对产物进行了柱纯化,所得产物在三氟化硼乙醚存在下用三乙基硅烷还原羰基,然后脱去三氟乙酰保护基,最后在盐酸存在下用甲醛闭环得到目标产物(10)。用NMR和MS表征了中间体和目标产物的结构。该合成反应条件温和,总收率为3．5％,产品纯度98．5％(HPLC)。     

熊果酸-3’-取代丙醇酯衍生物的合成及抗肿瘤活性研究

熊果酸与1,3-二溴丙烷反应制得中间体熊果酸-3’-溴代丙醇酯(1),含溴醇酯1与含氮化合物反应,合成了系列熊果酸含氮衍生物2a～2j,均未见文献报道,其结构经1H NMR,13C NMR,IR,MS确认.初步的抗肿瘤生物活性研究表明,部分化合物的抗肿瘤活性与熊果酸相比均有提高,其中化合物2e具有更强的抑制活性.