Determination of Camptothecin and 10-Hydroxycamptothecin in Camptotheca acuminata by LC-ESI-MS/MS

A rapid and sensitive liquid chromatography-tandem mass spectrometry method with multiple reaction monitoring was developed for the simultaneous determination of camptothecin and 10-hydroxycamptothecin in Camptotheca acuminata. The separation of camptothecin and 10-hydroxycamptothecin was performed on an Agilent Eclipse XDB-C18 column with a mixture of methanol and water (1:1, v/v) containing 0.2% formic acid as a mobile phase. The limits of detection of camptothecin and 10-hydroxycamptothecin were 4.0 ng/mL and 7.0 ng/mL (S/N = 3), respectively. Analysis took 10 minutes, making the method suitable for rapid determination of camptothecin and 10-hydroxycamptothecin in C. acuminata.     

Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins.

20(S)-Camptothecin derivatives having nitro, amino, chloro, bromo, hydroxyl and methoxyl groups in the A-ring were synthesized. B-Ring hydrogenated camptothecin (2a) was converted into 10-hydroxycamptothecin (6e) by treatment with lead tetraacetate in trifluoroacetic acid. 10-Substituted derivatives (6) were obtained by a photoreaction of N-oxides (9). The cytotoxicity of the A-ring modified camptothecins was evaluated against KB cells in vitro and leukemia L1210 in mice. 7-Ethyl-10-hydroxycamptothecin (6i) was identified as a potential derivative for further modification.     

Camptothecinoids from the seeds of Taiwanese Nothapodytes foetida

Two new alkaloids, 9-methoxy-18,19-dehydrocamptothecin (1) and 5- hydroxymappicine-20-O-beta-glucopyranoside (2a/2b as a racemic mixture), together with nine known compounds: camptothecin (3), 9-methoxy-camptothecin (4), 5-hydroxycamptothecin (5a/5b racemic mixture), 5-hydroxy-9-methoxycamptothecin (6a/6b racemic mixture), diosmetin (7), apigenin (8), apigenin-7-O-glucopyranoside (9), rosin (cinnamyl-O-beta-D-glucopyranoside) (10) and amarantholidoside IV (11) were isolated from the immature seeds of Nothapodytes foetida (Wight) Sleumer. The structures were elucidated by spectroscopic analyses. In the present research, compounds 1, 3, 4, 5a/5b and 6a/6b, also showed in vitro cytotoxicity against six cancer cell lines (HepG2, Hep3B, MDA-MB- 231, MCF-7, A549, and Ca9-22). Among them, compound 1 exhibited significant cytotoxicity against these cancer cell lines, with IC(50) of 0.24-6.57 microM. Furthermore, HPLC profiles were developed for qualitative and quantitative analysis of these active constituents in different parts of this plant, including mature and immature seeds, leaves, stems and roots. The results revealed that compounds 3 and 4 have the highest concentrations, which are found in the roots part of the plant.     

Determination of camptothecin and 10-hydroxycamptothecin in human plasma using polymer monolithic in-tube solid phase microextraction combined with high-performance liquid chromatography

A biocompatible in-tube solid-phase microextraction (SPME) device was used for the direct and on-line extraction of camptothecin and 10-hydroxycamptothecin in human plasma. Biocompatibility was achieved through the use of a poly(methacrylic acid-ethylene glycol dimethacrylate) monolithic capillary column for extraction. Coupled to high performance liquid chromatography (HPLC) with UV detection, this on-line in-tube SPME method was successfully applied to the simultaneous determination of camptothecin and 10-hydroxycamptothecin in human plasma. The calculated detection limits for camptothecin and 10-hydroxycamptothecin were found to be 2.62 and 1.79 ng/mL, respectively. The method was linear over the range of 10–1000 ng/mL. Excellent method reproducibility was achieved, yielding RSDs of 2.49 and 1.59%, respectively. The detection limit (S/N=3) of camptothecin was found to reach 0.1 ng/mL using fluorescence detection. The proposed method was shown to cope robustly with the extraction and analysis of camptothecin and 10-hydroxycamptothecin in plasma samples.     

20(S)-O-取代苯甲酸-7-乙基喜树碱酯类化合物的合成及其抗肿瘤活性

在AcOH/98％ H2S04体系中,喜树碱和正丙醛经烷基化反应制得7-乙基喜树碱(2);以1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐为脱水剂,4-二甲氨基吡啶为催化剂,2与取代苯甲酸直接酯化合成了一系列新型的20(S)-O-取代苯甲酸-7-乙基喜树碱酯类化合物(4a -4k),其结构经1H NMR,IR和MS表征.采用MTT法初步考察了4a～4k对人肺癌细胞(LLC-E9FP),人肺腺癌细胞(95D),人胃癌细胞(BGC-803),人胃癌细胞( HGC-27)和人肝癌细胞(7721)的抑制活性.结果表明,4b和4e对LLC-E9FP具有明显强于喜树碱的抑制活性;4h～4k对HGC-27,95D,7721也有明显的抑制活性.     

Synthesis and cytotoxic activity of 7-alkynyl camptothecin derivatives

Several 7-alkynyl camptothecin derivatives were prepared via Sonogashira coupling.And anti-tumor activities of these compounds were evaluated against human esophageal cancer cell line (Eca-109),human chronic myeloid leukaemia cell line (K562),bladder cancer cell line (5637) and gastric cell line (SGC7901).Compounds 9a-d and 10a exhibited remarkable in vitro cytotoxic activity,compared with topotecan.     

喜树碱及其衍生物的聚乙二醇化学修饰药物研究进展

目的：喜树碱及其衍生物药物是一类重要的抗肿瘤药物,但其存在水溶性差、生物利用度低、毒副作用大等问题,喜树碱及其衍生物的聚乙二醇化学修饰具有十分诱人的前景,但目前国内研究较少,本文综述近年来喜树碱及其衍生物药物的聚乙二醇化学修饰研究进展。方法：以喜树碱（Camptothecin, CPT）、伊立替康（Irinotecan, CPT-11）、7-乙基-10-羟基喜树碱（7-ethyl-10-hydroxycamptothecin, SN38）、聚乙二醇（Polyethylene glycol, PEG）、聚乙二醇化喜树碱（PEG-CPT）等为关键词,查阅近几年国内外相关研究文献。结果与结论：综述了喜树碱及其衍生物的聚乙二醇化学修饰药物的研究进展与临床研究报道,为发掘结构明确、组成稳定的新型化学修饰药物提供理论基础和技术支撑。     

四(对-乙酰氧醚-10-羟基喜树碱)苯基卟啉的合成及结构表征

设计并合成了一种卟啉类光敏剂与抗癌药羟基喜树碱通过共价键相连的四(对-乙酰氧醚-10-羟基喜树碱)苯基卟啉化合物. 通过紫外光谱、 红外光谱、 核磁氢谱和质谱分析等手段对其结构进行了表征. 在癌症治疗过程中目标化合物中2种药物可能起到一定的协同效应.     

Synthesis and platelet aggregation-inhibitory activities of novel 3-(2-oxopropylidene)azetidin-2-one derivatives. I

Treatment of (E)-3-(2-hydroxypropylidene)-4-methyl-1-phenylazetidin-2-one (11) with 10% Pd/C gave (E)-(12), (Z)-3-(2-oxopropylidene)-4-methyl-1-phenylazetidin-2-one (13), 3,4-cis-(14a) and 3,4-trans-3-(2-oxopropyl)-4-methyl-1-phenylazetidin-2-one (14b). Among them, 12 and 13 were found to show potent inhibitory activities against rabbit platelet-rich plasma aggregation induced by adenosine diphosphate or collagen. Ring-expanded homologous derivatives and an acyclic analogue of 12 were also synthesized and tested for the biological activities. The azetidin-2-one skeleton bearing a 2-oxoalkylidene moiety at the 3 position was found to be essential for the platelet aggregation inhibitory activities of these compounds.     

Hydroxycamptothecin deactivation rates and binding to model membranes and HSA determined by fluorescence spectra analysis

Camptothecins (CPTs) are fluorescent compounds exhibiting anticancer activity. They can exist in two forms, a lactone and a carboxylate. In neutral and base solution, lactone forms hydrolyse and convert into carboxylates. Only the lactone forms of CPTs are biologically active. Because of strong affinity of the carboxylate form of the parent drug camptothecin to human serum albumin (HSA), this protein promotes the deactivation of this compound. On the other hand, the lactone forms of camptothecins do not hydrolyse and are stabilized when bound to membranes. The following three hydroxycamptothecins, 10 hydroxycamptothecin (10-OH-CPT), 7-ethyl-10-hydroxy-camptothecin (SN-38) and 7-tert-butyldimethylsil-10-hydroxycamptothecin (DB-67) were studied. Factor analysis of a set of fluorescence excitation spectra recorded during lactone hydrolysis facilitated the high-throughput determination of the deactivation rates of camptothecin and each hydroxycamptothecin in phosphate buffered saline. The fluorescence spectra of hydroxycamptothecins diluted in HSA solution or suspended in DMPC liposomes were recorded, and the association constants of these drugs to membranes and plasma proteins were calculated. Among the analysed agents, DB-67 exhibited the most desirable properties including low affinity of the carboxylate form for albumin and high affinity of its lactone form for model membranes.     

Comparative studies on the camptothecin content from Nothapodytes foetida and Ophiorrhiza species

Camptothecin is an anticancer quinoline alkaloid effective against colon cancer. It acts by inhibition of the enzyme DNA topoisomerase I. A comparative study of camptothecin from the indigenous plants namely Nothapodytes foetida, Ophiorrhiza mungos and Ophiorrhiza rugosa indicated highest yields of camptothecin and 9-methoxy camptothecin in N. foetida. The other two plants O. mungos and O. rugosa contained low levels of alkaloids.     

In vitro cytotoxicity activity on several cancer cell lines of acridone alkaloids and N-phenylethyl-benzamide derivatives from Swinglea glutinosa (Bl.) Merr

The methanol extract from the stems and fruits of Swinglea glutinosa (Rutaceae) afforded 11 known acridone alkaloids and three N-phenylethyl-benzamide derivatives, glycocitrine-IV, 1,3,5-trihydroxy-4-methoxy-10-methyl-2,8-bis(3-methylbut-2-enyl)acridin-9(10H)-one, 1,3,5- trihydroxy-2,8-bis(3-methylbut-2-enyl)-10-methyl-9-acridone, citbrasine, citrusinine-II, citrusinine-I, 5-dihydroxyacronycine, pyranofoline, 3,4-dihydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-2H-pyrano[2,3-a]acridin-12(7H)-one, 2,3-dihydro-4,9-dihydroxy-2-(2-hydroxy-propan-2-yl)-11-methoxy-10-methylfuro[3,2-b]acridin-5(10H)-one, bis-5-hydroxyacronycine, N-(2-{4-[(3,7-dimethylocta-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, N-(2-{4-[(3,7-dimethyl-4-acethyl-octa-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, and severine acetate. All compounds isolated were examined for their activity against three cancer cell lines: human lung carcinoma (COR-L23), human breast adenocarcinoma (MCF7), human melanoma (C32), and normal human fetal lung cell line, MRC-5. The acridones tested exhibited weak cytotoxicity but the amides showed moderate nonselective cytotoxic activity.     

Three new podocarpane-type diterpenoids from callus of Securinega suffruticosa

Three new podocarpane-type diterpenoids, 3beta,12-dihydroxy-13-methyl-6,8,11,13-podocarpatetraen (1), 3beta,12-dihydroxy-13-methyl-5,8,11,13-podocarpatetraen-7-one (2), and 1-(7-hydroxy-2,6-dimethyl-1-naphthyl)-4-methyl-3-pentanone (3) (20(10-->5)-abeo-4,5-seco-5(10),6,8,11,13-podocarpapentaen-3-one) were isolated from callus of Securinega suffruticosa. The structures were elucidated by spectroscopic methods. Compounds 1, 2, and 3 showed cytotoxic activity against five human cancer cell lines (A549, BEL 7402, BGC-823, HCT-8, A2780).     

Conversion of Camptothecins to Mappicine Ketones Using Silica Gel Supported Sodium Hydrogen Sulfate Catalyst

Silica gel supported sodium hydrogen sulfate (NaHSO₄.SiO₂) catalyst has been utilized for the conversion of camptothecin and 9-methoxycamptothecin to mappicine ketone, an antiviral lead compound and its analogue, 9-methoxymappicine ketone respectively.     

Constructing conformationally constrained macrobicyclic musks

To investigate the structure-odor correlation of musks, (12R)-12-methyl-13-tridecanolide (1), a macrocyclic musk, and 13-tridecanolide, its non-musky demethyl analogue, were conformationally constrained by introduction of methylene bridges between C-3 and C-8 or C-9. These [7.5.1]- and [8.4.1]-macrobicycles were synthesized starting from bicyclo[5.3.1]undec-8-en-9-one (3) and bicyclo[4.3.1]dec-7-en-8-one (8), respectively, by a sequence consisting of catalytic hydrogenation, alpha-alkylation with a TBS-protected (tert-butyldimethylsilyl) hydroxy halide, acid-catalyzed cyclization, oxidative cleavage of the formed enol ether double bond, and subsequent reduction of the carbonyl group via its tosylhydrazone. The compound (1R,6R,9R)-(+)-6-methyl-4-oxa-bicyclo[7.5.1]pentadecan-3-one (22) was found to possess the most pronounced musk odor, and this was rationalized by a superposition analysis with the polycyclic aromatic musk odorant (4S,7R)-Galaxolide (2). In its (1S,6R,9S)-(+)-stereoisomer 23 as well as in (1S,6R, 10R)-(+)-6-methyl-4-oxabicyclo[8.4.1]-pentadecan-3-one (18) the (6R)-methyl group seems to hinder the interaction with the musk receptor, while the demethyl compounds 7 and 12 showed only very faint odors.     

拓扑替康中三个有关物质的合成

采用易得的原料、简单的化学方法和方便的操作,设计了新的合成路线,制备了拓扑替康药物报批中的三种相关杂质。分别由拓扑替康盐酸盐(1)经游离、酯水解开环反应制备得到了拓扑替康羧酸钠盐(2),由拓扑替康(11)经正丙醇取代反应制备得到9-丙氧甲基-10-羟基喜树碱(4),以及由10-羟基喜树碱(5)经羟甲基化反应制备得到9-羟甲基-10-羟基喜树碱(3)。     

Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin

Novel 36 derivatives (6), bonding the phenolic hydroxyl group of 7-ethyl-10-hydroxycamptothecin (4) with diamines through a monocarbamate linkage, were synthesized and their antitumor activity was evaluated in vivo. The derivatives were soluble in water as their HCl salts with the E lactone ring intact and exhibited significant antitumor activity. One of the derivatives, 6-27 showed excellent activity against L1210 leukemia and other murine tumors. The structure of its hydrochloride trihydrate (CPT-11) was determined by spectroscopic and crystallographic methods.     

High-throughput detection of drugs binding to proteins using desorption electrospray ionization mass spectrometry

In this paper, we present a strategy for screening drugs that bind to proteins by combining centrifugal filtration with desorption electrospray ionization mass spectrometry (DESI-MS). Membrane filtration was used to remove any unbound drugs. Then, drug–protein complexes deposited on the DESI substrate were dissociated during the DESI-MS analytical process, and the liberated drugs were measured. To validate the methodology, the screening of a series of drugs against two types of proteins was performed. Three DNA topoisomerase I (Topo I) inhibitors (camptothecin (CPT), hydroxycamptothecin (OHCPT) and 7-ethyl-10-hydroxycamptothecin (SN-38)) were screened against Topo I and the DNA-Topo I complex using DESI-MS. The results indicated that none of the inhibitors bound to Topo I, because the inhibitors had binding affinities only to the DNA-Topo I complex. Among the three drugs that bound to the DNA-Topo I complex, SN-38 had the strongest relative binding affinity, and CPT had the weakest relative binding affinity. The impact of the DESI spray solvent composition on the analysis of drug–protein complex binding was evaluated. Seven alkaloid drugs were also screened against Topo I using DESI-MS. Berberine and palmatine had good binding affinities. A screening of 21 types of drugs was carried out to determine whether the drugs bound to human serum albumin (HSA). The DESI-MS screening process could be achieved within 1.75 min. The study provides a method to qualitatively detect compounds that bind to proteins, showing great potential in drug design and screening.     

The synthesis of the monomethylbenzo[2,3]phenanthro-[4,5-bcd]thiophenes

The synthesis of the potentially mutagenic 1-methyl- (11), 3-methyl- (12), 4-methyl- (21), 5-methyl- (27), 7-methyl- (58), 8-methyl- (61), 9-methyl- (59) and 10-methylbenzo[2,3]phenanthro[4,5-bcd]thiophene (60) is reported.     

20(S)-O-喜树碱肉桂酸酯衍生物的合成及其抗肿瘤活性研究

为了提高喜树碱内酯环的稳定性降低其毒性, 增加其抗肿瘤效能, 以喜树碱为先导化合物, 通过酯化反应直接合成了17个20(S)-喜树碱肉桂酸酯衍生物, 并采用MTT法测定了对于人胃癌细胞SGC-7901的体外抗肿瘤活性, 活性测试结果表明有些化合物的抑制活性明显高于母体化合物喜树碱.