Synthesis and anticancer activity of fluorinated analogues of combretastatin A-4

The synthesis of a series of fluorinated benzaldehydes and their use in the Wittig synthesis of fluoro-substituted stilbenes is described. 3,5-Difluoro-4-hydroxybenzaldehyde (6) and 3-fluoro-4-methoxybenzaldehyde (11) are prepared by Duff formylation of 3,5-difluorophenol and 2-fluoroanisole, respectively. 2-Methoxy-3,4-difluorobenzaldehyde was obtained by Friedel-Crafts formylation of 2,3-difluoroanisole with α,α-dichloromethyl methyl ether. The aldehydes were used to make a series of fluorinated analogues of the anticancer combretastatins A-1, A-2 and A-4. The in vitro anticancer properties of the fluoro combretastatins are reported. The most active fluoro analogue 3-deoxy-3-fluoro-combretastatin A-4 (Z-2) retains the potent cell growth inhibitory properties of CA-4.     

Synthesis,modeling, and biological studies of new thiazole-pyrazole analogues as anticancer agents

A series of various substituted thiazole-pyrazole hybrids 5, 7, 8, and 9 were synthesized, and their chemical structures were confirmed by spectral data (infrared, ¹H & ¹³C NMR and Mass). The frontier molecular orbital structural and energetic properties of the targeting thiazole-pyrazole hybrids were explored using the DFT/B3LYP methodology. The data indicated that they had a low energy gap (ΔE_H-L), 1.51–2.42 eV, and may be sorted as 6 < 9 < 7 < 8 < 4 < 3 < 5. The synthesized thiazole-pyrazole hybrids were explored for their activities towards HepG2, MCF-7, and HCT-116 in contrast to doxorubicin. The newly synthesized thiazole-pyrazole analogues demonstrated an acceptable efficiency towards the HepG2 cancer cell line in accordance with this order: 8 > 9 > 7 > 6. Meanwhile, most of the synthesized analogues displayed a significant reduction for the activity of the CAIX inhibitor, with IC₅₀ = 0.071 ± 0.015 to 0.902 ± 0.043 µM. Likewise, they revealed an IC₅₀ = 0.119 ± 0.043 to 0.906 ± 0.04 µM for CAXII inhibitor. Moreover, the newly synthesized thiazole-pyrazole analogues were exposed to the theoretical molecular docking study with PDB:1RHJ as the crystal structure of caspase-3 to examine their antiapoptotic effect as well as their certain properties on the caspase-3 enzyme.     

Design and synthesis of 3,5-disubstituted boron-containing 1,2,4-oxadiazoles as potential combretastatin A-4 (CA-4) analogs

We have designed and synthesized a small library of 3,5-disubstituted-1,2,4-oxadiazole containing combretastatin A-4 (CA-4) analogs. Our objective is to increase the efficacy of the CA-4 as an anti-tubulin and antimitotic agent by substituting the cis-alkene bond with one of its bioisosteres, the 1,2,4-oxadiazole ring. We also modified the substituents attached to both of the phenyl rings (ring A and B in Fig. 1) of CA-4 for the purpose of diversifying our analogs based on SAR. These compounds were synthesized via a coupling reaction between an amidoxime and a carboxylic acid in DMF solvent, with HOBt as a base, and utilizing EDCI as a coupling reagent. Using this protocol, we synthesized a small library of 10 compounds with moderate to good yields. A detailed biological study is currently undergoing in our laboratory to evaluate the activity of these compounds.     

Design,synthesis and anti-proliferative effects in tumor cells of new combretastatin A-4 analogs

A total of 11 novel combretastatin A-4(CA-4) analogs were designed, synthesized, and evaluated for the anti-proliferative effects in tumor cells. The compounds represent four structural classes:(i)hydrogenated derivatives,(ii) ethoxyl derivatives,(iii) amino derivatives and(iv) pro-drugs. Biological evaluations demonstrate that multiple structural features control the biological potency. Three of the compounds, sit-1, sit-2 and sit-3, have potent anti-proliferative activity against multiple cancer cell lines. Their pro-drugs were synthesized to increase water solubility. Structure–activity relationship study and Surflex-Docking were studied in this paper. These results will be useful for the design of new CA-4 analogs that are structurally related to the SAR study.     

An acyclic enediyne anticancer compound attributed to a Bergman cyclization at physiological temperature

Enediyne cytotoxic drugs have attracted much attention because of their unique structure and potent anticancer activity. However, acyclic enediynes are long considered as inactive at physiological temperature due to their long C1-C6 distance. By adjusting the steric bulkiness of the functional groups at the alkynyl termini and the electron-withdrawing effect at the ene moiety, herein, a simple acyclic enediyne was designed and synthesized to achieve the onset of thermal Bergman cyclization at physiological temperature in polar solvents. The spontaneous generation of diradical intermediates was confirmed through EPR analysis and further supported by spin trapping experiment, radical indicator experiment, and high resolution MS analysis. The reactive diradicals generated in aqueous media induced single and double stranded cleavage of DNA, and showed high cytotoxicity to Hela cells. The IC₅₀ value of the enediyne compound is comparable to many clinical used anti-tumor agents.     

Synthesis of functionalized aminopyrazole and pyrazolopyrimidine derivatives: Molecular modeling and docking as anticancer agents

Three new functionalized 4-aminopyrazole derivatives were synthesized and cyclized with phenyl isothiocyanate to yield the corresponding three pyrazolo[4,3-d]pyrimidine analogues. The DFT quantum chemical calculations were utilized in the determination of the frontier molecular orbital energies and Fukui’s indices. The data showed that they have a low HOMO-LUMO energy gap, ranging from 1.16 to 2.35 eV for 5 and 6, respectively. The newly created analogues' cytotoxic qualities were evaluated in comparison to the reference 5-florouracil (5-Fu) using an in vitro MTT cytotoxicity screening investigation toward four different cell lines, including HCT-116, HepG2, MCF-7, and WI38. The results showed variable potency against human cell lines, with MCF-7 and HepG-2 showing cytotoxic selectivity. The most potent agent against MCF-7 and HCT-116 human cancer cells were found to be aminopyrazole and pyrazolopyrimidine derivatives 4–9. The structure–activity relationships (SAR) for the synthesized compounds were discussed. The examined compounds had superior cytotoxic properties; the most potent derivative 7, had an IC₅₀ ranged from 11.51 ± 0.35 to 21.25 ± 0.37 µM. Meanwhile, quantum chemical computation used independent variables E_H, E_L, ΔE_H-L, χ and η were applied to determine the best way to describe activity. As a result, an increase in the HOMO-LUMO gap and hardness will result in an increase in the anticancer activity. While the E_H, E_L, and showed negative coefficients, increasing them will decrease the anticancer activity. Furthermore, 5IVE protein's crystal structure for KDM5A was docked with the newly created aminopyrazole and pyrazolopyrimidine derivatives to afford the theoretical prediction on the KDM5A enzyme.     

Synthetic approach to analogues of betulinic acid

2-Methylcyclohexane-1,3-dione 14 was converted via the Wieland-Miescher analogue 15 into the 6-silyloxy-2,5,5,8a-tetramethyldecalin-1-one 21 by an efficient process. Several routes were examined to transform this compound into the pentacyclic triterpene skeleton of betulinic acid and its structural analogues. For example, the iodide 39, easily prepared from 21, was converted via a Sonogashira-hydroboration-Suzuki process into the E-triene 45. Photolysis of 45 using a benzanthrone sensitizer afforded the Z-triene 43. However, all attempts at effecting the cyclization of this triene 43 to the cyclohexadiene 47 (electrocyclic via photochemical or thermal means, metal-catalyzed processes, oxidative and radical cyclizations) failed to produce the key pentacyclic material.     

Synthesis and Cytotoxic Activity of Novel Water-soluble Prodrugs of Combretastatin A-4

Combretastatin A-4 (CA4) 1 is a natural product isolated from the bark of a South African tree Combretum caffrum1-3. This substance is a potent antimitotic agent and can strongly inhibit the polymerization of tubulin by binding to the colchicine-binding s…     

Tandem Heck-Suzuki-Miyaura reaction: Application to the synthesis of constrained analogues of combretastatin A-4

A series of compounds related to combretastatin A-4 has been synthesized by a tandem Heck-carbocyclization/Suzuki coupling process. From various alkynamides and 3,4,5-trimethoxyphenyl boronic acid or the corresponding styryl derivative, (E)-3-arylmethyleneoxindoles (type I) and (EE)-3-alkylideneoxindoles (type II) were efficiently obtained in a stereoselective manner. Factors influencing yield and stereoselectivity are detailed.     

Combretastatin A-4 全合成中的光化学Wittig反应

在天然产物Combretastatin A-4全合成的关键步骤——Wittig反应中,引入紫外(254nm)辐射,结果使得Wittig反应的产率从原有的65％提高到83．6％。特别是其产物的Z-式立体异构体选择性大大提高,从原来的Z／E之比为3．6提高到11．5,笔者推测这种光化学反应是按双自由基机理进行。     

天然产物Combretastatin A-1和Combretastatin B-1的合成

基于Perkin反应策略合成了具有强效抗肿瘤、抗血管活性的天然产物Combretastatin A-1(CA1)和Combretastatin B-1(CB1).以2,3,4-三羟基苯甲醛(1)为起始物, 经单甲基化反应得到2,3-二羟基-4-甲氧基苯甲醛(2), 再经酚羟基保护得到2,3-二异丙基-4-甲氧基苯甲醛(3), 该化合物与3,4,5-三甲氧基苯乙酸(4)发生Perkin反应分离得到E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二异丙氧基-4'-甲氧基)丙烯酸(E-5), 经脱羧反应得到Z-3,4,4',5-四甲氧基-2',3'-二异丙氧基二苯乙烯(6), 最后经脱保护反应得到CA1.另外, 将E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二异丙氧基-4'-甲氧基)丙烯酸(E-5)脱去保护基得到E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二羟基-4'-甲氧基)丙烯酸(7), 该化合物经脱羧-异构化反应得到E-3,4,4',5-四甲氧基-2',3'-二羟基二苯乙烯(E-CA1), 最后经催化氢化得到CB1.     

壳聚糖基多功能纳米药物载体的体外研究

制备了一种壳聚糖基多功能纳米药物载体系统, 并探讨了其体外释药性质. 合成了甲氨蝶呤-壳聚糖偶联物(MTX-CS), 甲氨喋呤(MTX)的取代度为6.3%; MTX-CS具有两亲性, 在水性介质中能自组装形成纳米粒子, 平均粒径为(269.5±18.3) nm, zeta电位为(25.7±0.9) mV. MTX-CS纳米粒子能有效包载抗血管生成药Combretastatin A-4(CA-4), 当药物/载体材料投料比为1∶4 时, 载药量为15.7%, 包封率为62.8%. 体外释放实验结果显示, CA-4释放较快, MTX释放缓慢, 有利于发挥2种药物的协同抗肿瘤作用.     

Synthesis and evaluation of nitrate derivatives of colchicine as anticancer agents

To search for more potent antitumor agent,a series of novel nitric oxide-donating colchicine(Col) derivatives(6a-f,8a and b) were synthesized by coupling nitrates with N-methyl colchiceinamide.Their cytotoxicity against four human cancer cell lines in vitro were evaluated by MTT assay.It was found that many of the derivatives displayed significant activity,particularly,compounds 6c,8a and 8b showed more potent cytotoxic activities than Col.     

Simplified aminocoumarin analogues as anticancer agents： Amino isosteric replacement in the noviose moiety resulted in substantial enhancement of antiproliferative activity

Simplified aminocoumarin analogues,either noviosylated or simple basic heterocycle attached 3-amido-coumarin compounds,are known to be promising anticancer agents targeting the C-terminal ATP-binding site of Hsp90.In this study,3’-amino isosteric replacement in the noviose moiety of two known noviose containing Hsp90 C-terminal inhibitors was synthetically realized for the first time.In vitro evaluation of these compounds suggested that the introduction of a basic amino group into the noviose subunit resulted in significant improvement of their cytotoxicities.     

One-pot hydrosilylation-protodesilylation of functionalized diarylalkynes: a highly selective access to Z-stilbenes. Application to the synthesis of combretastatin A-4

An efficient stereoselective synthesis of Z-stilbenes has been developed from diarylalkynes via a new hydrosilylation-protodesilylation process. The scope and limitation of this method is presented to stereoselectively prepare a wide range of (Z)-stilbenes in a one-pot way is presented. A concise application to the preparation of combretastatin A-4 (CA-4), a vascular targeting agent inhibitor of tubulin polymerisation is described.     

Synthesis and biological evaluation of nitric oxide-releasing sixalkoxyl biphenyl derivatives as anticancer agents

A series of novel nitric oxide-donating sixalkoxyl biphenyl derivatives （14a-1） were synthesized by coupling furoxan with alkoxyl biphenyl skeleton using amino acids as the spacers, and their cytotoxicity against HepG2 cells in vitro were evaluated by MTT method. It was found that 14c, 14d, 14f, 14i, 14j and 14k showed more potent cytotoxic activities than control 5-fluorouracil. NO release assay of target compounds indicated that the maximum amount of NO released by most active compounds 14c and 14j was about 6 × 10^-2 μmol/L, whereas 14a and 14h with very weak activity only released NO of 1 × 10^-2 μmol/L.     

Synthesis and preliminary cytotoxic evaluation of substituted indoles as potential anticancer agents

A variety of indole derivatives were designed,synthesized and preliminarily evaluated for their in vitro cytotoxic activity in the A431 and H460 cell lines.All the compounds examined conferred unusual potency in a tumor cell cytotoxicity assay.The findings showed the indole derivatives would be a promising candidate for the development of new anticancer agents.     

Synthetic approach to analogues of the original structure of sclerophytin A

A route to analogues of the original structure of sclerophytin A is described. The beta-anomer of dideoxyribosyl nitriles 10a,b (prepared from glutamic acid) was converted into the methyl ketone 11. Addition of a silylated acetylide to 11 in diethyl ether/trimethylamine gave mainly 22a. Alkylation with methallyl halide and ozonolysis gave the ketone 24, which was then converted by hydrogenation and a second ozonolysis into the keto aldehyde 26. A two-step aldol process afforded the desired 3-pyrone 27 in good overall yield. However, several methods for the conversion of this enone 27 into the desired sclerophytin analogue 2 failed.     

Synthesis and cytotoxicity screening of derivatives of the simplified ecteinascidin pentacyclic skeleton as anticancer agents

A series of new ecteinascidin pentacyclic-derived compounds bearing aryl carboxylic amide side chains at C-22 have been designed and synthesized. The cytotoxicity evaluation confirmed their potent antitumor activity by use of eight different cell lines. Studies on the structure-activity relationship of them showed that the chemical structure of C-22 pendants have great effects on the tumor-killing activity. Notably, Compounds 6, 7 and 8 with benzo[b]thiophene-2-carboxamide pendants exhibited excellent broad-spectrum antitumor activity with the low IC₅₀ values of 10^?7?M.