- Host–guest systems based on pH-sensitive acyclic cucurbit[n]urils for controlled release of camptothecin
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Stimuli-responsive drug delivery systems may provide an effective way to treat cancer as they can release cargoes regularly according to changes in the human microenvironment. In this work, we design and prepare acid-controlled release complexes of camptothecin with three pH-sensitive acyclic cucurbit[n]urils. The inclusion complexes have been characterized by 1H and 2D nuclear magnetic resonance, X-ray powder diffraction, and phase solubility diagram. Cells incubated with complexes have been analyzed by high-content analysis, and cytotoxicity tests have been completed by MTT assay. The results showed that complexes with different binding constants can release the drug substance in the physiological pH environment of cancer cells, maintain good anticancer activity, and have low cytotoxicity. This provides a strategy about targeted and responsive systems of CPT for clinical application.
- Lin, Jieling,Yang, Lei,Liao, Xiali,Gao, Chuanzhu,Yang, Bo
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- A practical six-step synthesis of (S)-camptothecin
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(Matrix Presented) An asymmetric synthesis of (S)-camptothecin (1) has been accomplished in six steps starting from two commercially available heterocycles.
- Comins, Daniel L.,Nolan, Jason M.
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- Synthetic studies on camptothecins. Part 1: An improved asymmetric total synthesis of (20S)-camptothecin
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A six-step asymmetric total synthesis of (20S)-camptothecin (1) has been accomplished in 25% overall yield starting from the known pyridone 3. The key steps in this synthesis are the chemoselective Ni-catalyzed hydrogenation of 3-cyanopyridone 6 to 3-formylpyridone 7 in AcOH/pyridine/H2O and the Davis asymmetric hydroxylation of tricyclic lactone 4 utilizing a chiral N-sulfonyloxaziridine into (4′S)-tricyclic hydroxylactone 2.
- Zhang, Li-Peng,Baoa, Yong,Kuang, Yun-Yan,Chen, Fen-Er
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- Synthesis and antitumor activity of a series of lactone-opened camptothecin derivatives
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A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.
- Zheng, Chao,Li, Ming-Zong,You, Tian-Pa,Tang, Wei-Ping,Lou, Li-Guang
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- Kinetic and thermodynamic characterization of camptothecin hydrolysis at physiological pH in the absence and presence of human serum albumin
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To accurately derive the kinetic and thermodynamic parameters governing the hydrolysis of the lactone ring at physiological pH, a derivative spectrophotometric technique was used for the simultaneous estimation of lactone and carboxylate forms of camptoth
- Thakur, Rishi,Kunadharaju, Sasank,Savva, Michalakis
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- Kinetics and mechanisms of activation of α-amino acid ester prodrugs of camptothecins
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The α-amino acid ester prodrugs of the antitumor agent camptothecin and a more potent, lipophilic silatecan analogue, DB-67, have been shown by NMR spectroscopy and quantitative kinetic analyses to undergo quantitative conversion to their pharmacologically active lactones via a nonenzymatic mechanism that at pH 7.4 is favored over direct hydrolysis. The alternate pathway involves the reversible intramolecular nucleophilic amine attack at the camptothecin E-ring carbonyl to generate a lactam (I) followed by a second intramolecular reaction to produce a bicyclic hemiortho ester (I′). The intermediates were isolated and shown to exist in an apparent equilibrium dominated by the hemiortho ester in DMSO using NMR spectroscopy. The conversion of prodrugs of camptothecin or DB-67 containing either α-NH2 or α-NHCH3 and their corresponding hemiortho esters were monitored versus time in aqueous buffer (pH 3.0 and 7.4) at 37 °C, and the kinetic data were fit to a model based on the proposed mechanism. The results indicated that while the prodrugs are relatively stable at pH 3, facile lactone release occurs from both the prodrugs and their corresponding hemiortho ester intermediates under physiological conditions (pH 7.4). The glycinate esters and their hemiortho esters were found to be more cytotoxic than the JV-methylglycinates or their corresponding hemiortho ester intermediates in vitro using a human breast cancer cell line (MDA-MB-435S), consistent with their more rapid conversion to active lactone. The pH dependence of the nonenzymatic pathway for conversion of these α-amino acid ester prodrugs suggests that they may be useful for tumor-targeting via liposomes, as they can be stabilized in an acidic environment in the core of liposomes and readily convert to the active lactone following their intratumoral release.
- Song, Lin,Bevins, Robert,Anderson, Bradley D.
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- Asymmetric syntheses of (+)-camptothecin and (+)-7-ethyl-10- methoxycamptothecin
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Total syntheses of (+)-camptothecin (1a) and (+)-7-ethyl-10- methoxycamptothecin (1b) from racemic ethyl 1-ethoxycarbonyl-3-oxopyrrolidin- 2-ylacetate (7) were accomplished via asymmetric hydroxylation onto C20 of racemic 20-deoxycamptothecin derivatives (3a,b) employing a chiral Davis reagent, (2R, 8aS)-(+)-(camphorylsulfonyl)oxaziridine.
- Tagami, Keiko,Nakazawa, Norio,Sano, Shigeki,Nagao, Yoshimitsu
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- A CAMPTOTHECIN DERIVATIVE FROM NOTHAPODYTES FOETIDA
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A novel comptothecin derivative was isolated from the wood of Nothapodytes foetida.Its structure was elucidated by spectral data as (20S)-18,19-dehydrocamptothecin.
- Aiyama, Ritsuo,Nagai, Hisako,Nokata, Kenichiro,Shinohara, Chigiru,Sawada, Seigo
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- Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy
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An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.
- Liu, Qian,Liu, Minjie,Huang, Guangxin,Chen, Fen-er
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- Hydrogean Peroxide Inducible Acid-Activatable Prodrug for Targeted Cancer Treatment
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Because some of the potentially most useful boronic acids are inherently unstable in blood plasma and exhibit poor selective retention in tumours, 2-heterocyclic N-methyliminodiacetic acid (MIDA) boronates provide a stable, spacious and highly effective harbor for prodrug conjugates. Herein we report MIDA boronates in conjunction with naphthalene-based fluorophores as suitable compounds for tumour diagnosis by virtue of their remarkable specificity and uniform benchtop stability. The shielding group was found to be effective at imparting stability under physiological conditions (pH 7.4), with rapid release of the drug upon exposure to the acidic microenvironment of the tumor. This approach significantly enhanced the efficiency of drug release and was found to exhibit fewer side effects, thus indicating its great potential for precision therapeutics.
- Liu, Jun,Wang, Jinhua,Si, Shuang,Xu, Jinyi,Xue, Peng
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- Mechanochemical activation of disulfide-based multifunctional polymers for theranostic drug release
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Drug delivery systems responsive to physicochemical stimuli allow spatiotemporal control over drug activity to overcome limitations of systemic drug administration. Alongside, the non-invasive real-time tracking of drug release and uptake remains challenging as pharmacophore and reporter function are rarely unified within one molecule. Here, we present an ultrasound-responsive release system based on the mechanochemically induced 5-exo-trigcyclization upon scission of disulfides bearing cargo molecules attachedviaβ-carbonate linker within the center of a water soluble polymer. In this bifunctional theranostic approach, we release one reporter molecule per drug molecule to quantitatively track drug release and distribution within the cell in real-time. We useN-butyl-4-hydroxy-1,8-naphthalimide and umbelliferone as fluorescent reporter molecules to accompany the release of camptothecin and gemcitabine as clinically employed anticancer agents. The generality of this approach paves the way for the theranostic release of a variety of probes and drugs by ultrasound.
- Shi, Zhiyuan,Song, Qingchuan,G?stl, Robert,Herrmann, Andreas
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p. 1668 - 1674
(2021/02/22)
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- Visible-Light-Induced Radical Cascade Cyclization: Synthesis of (20S)-Camptothecin, SN-38 and Irinotecan
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(20S)-Camptothecin, irinotecan and SN-38 were successfully synthesized by a photocatalyzed radical cascade cyclization from an N-propargyl iodopyridinone and an arylisonitrile under visible light with a ruthenium catalyst. This synthetic method provided a useful entry into composing camptothecin family of antitumor agents in good yields under mild reaction conditions without the use of heavy metal reagents.
- Yuan, Yao,Dong, Wuheng,Gao, Xiaoshuang,Xie, Xiaomin,Curran, Dennis P.,Zhang, Zhaoguo
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p. 1035 - 1040
(2018/09/25)
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- Tetrazine-mediated bioorthogonal prodrug-prodrug activation
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The selective and biocompatible activation of prodrugs within complex biological systems remains a key challenge in medical chemistry and chemical biology. Herein we report, for the first time, a dual prodrug activation strategy that fully satisfies the principle of bioorthogonality by the symbiotic formation of two active drugs. This dual and traceless prodrug activation strategy takes advantage of the INVDA chemistry of tetrazines (here a prodrug), generating a pyridazine-based miR21 inhibitor and the anti-cancer drug camptothecin and offers a new concept in prodrug activation.
- Neumann, Kevin,Gambardella, Alessia,Lilienkampf, Annamaria,Bradley, Mark
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p. 7198 - 7203
(2018/10/02)
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- An improved synthesis of (20S)-camptothecin and its analogue via an asymmetric α-hydroxylation with a chiral organocatalyst
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An efficient and stereocontrolled synthesis of (20S)-camptothecin and an analogue has been developed. The key feature of this synthesis is the organocatalyzed asymmetric α-hydroxylation of the lactone precursor 4 to construct its stereocenter, providing tricyclic hydroxylactone 2 in 90% yield and with 88% enantioselectivity. The precursor 4 was efficiently synthesized from the known pyridine 5 in three steps.
- Wang, Xinlong,Xu, Lingjun,Xiong, Fangjun,Wu, Yan,Chen, Fener
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p. 843 - 848
(2017/06/13)
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- Synthesis of indolizinoquinolinones through three- and four-component domino Knoevenagel / hetero-Diels–Alder reactions: novel access to (+)-camptothecin
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[Figure not available: see fulltext.] The fused heterocyclic indolizinoquinolinone system is a key structural feature of several highly bioactive alkaloids, including camptothecin. Camptothecin has been efficiently obtained by a three- or four-component domino Knoevenagel / hetero-Diels–Alder reaction of aldehyde, Meldrum's acid, and enol ether in the presence or absence of alcohol, followed by reductive cleavage of the amine protecting group. The obtained products were further transformed along several different routes leading to camptothecin.
- Tietze, Lutz F.,Bischoff, Matthias,Khan, Taukeer A.,Liu, Deshan
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p. 434 - 445
(2017/07/07)
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- A two-photon-activated prodrug for therapy and drug release monitoring
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A light-activated cleavage strategy for the concomitant release of active drugs and generation of fluorescence changes is highly desirable. Herein a molecular prodrug featuring real-time monitoring of drug localization and release by manipulating fluorophores has been created by constructing a cleavable structure which comprises a photoremovable coumarinyl, an anticancer drug camptothecin, a cleavable linker and a near infrared fluorescent dye dicyanomethylene-4H-pyran (DCM). The fluorescence of coumarinyl and CPT is completely quenched by the DCM moiety via fluorescence resonance energy transfer (FRET). The internalization of the prodrug by cells and its subsequent intracellular location can be tracked by collecting the red fluorescence of DCM; while the release of active CPT as a result of one- or two-photon irradiation can be monitored by observing the newly emerged fluorescence of CPT under one- or two-photon excitation. The prodrug also shows highly controllable cytotoxicity toward HeLa cells and A549 cells, with low IC50 values of 4.01 and 2.53 μM, respectively, upon light irradiation and with much higher IC50 values (>40 μM) without light irradiation. This strategy may provide an approach for the development of light-activatable theranostic anticancer therapeutics.
- Liu, Peilian,Li, Bowen,Zhan, Chenyue,Zeng, Fang,Wu, Shuizhu
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p. 7538 - 7546
(2017/09/27)
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- Total Synthesis of Camptothecin and Related Natural Products by a Flexible Strategy
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A flexible strategy for constructing natural products containing indolizinone or quinolizinone scaffolds and their analogues was developed, which was based on a cascade exo hydroamination followed by spontaneous lactamization. This method was applied in the total synthesis of camptothecin in nine steps in a new ring-forming approach. It was also used to efficiently prepare five biogenetically or structurally related natural alkaloids, including 22-hydroxyacuminatine, oxypalmatine, norketoyobyrine, naucleficine, and nauclefine, as well as 35 natural-product-like molecules. We believe that this method and the small-molecule library prepared with it can open new avenues for studying the bioactivity of camptothecin and Nauclea natural products.
- Li, Ke,Ou, Jinjie,Gao, Shuanhu
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supporting information
p. 14778 - 14783
(2016/11/23)
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- A synthetic camptothecin compound in 5-6 method of and ring structure (by machine translation)
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The present invention discloses a synthetic camptothecin compound in the 5 [...] 6 method of and ring structure, the method is that the conjugated structure of formula II occurs in the solvent alkene alkyne ester series cyclization reaction in the molecule, thus the system results in the type shown in I of the 5 [...] 6 and ring structure, the specific equation is: In the formula: R 1 and R 2 are respectively and independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic group; or, R 1 and R 2 together form a saturated or unsaturated carbocyclic or heterocyclic; R 3 and R 4 are respectively and independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic group; or, R 3 and R 4 together form a saturated or unsaturated carbocyclic or heterocyclic rings; selected from R C 1-C 4 alkyl; P is amino protecting group. The stated method of this invention has the advantages of simple operation, safety and environmental protection, low production cost, high yield, is suitable for large-scale production, and the like, to promote such compounds in the medical field with the extensive application of an important value. (by machine translation)
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- A Glutathione (GSH)-Responsive Near-Infrared (NIR) Theranostic Prodrug for Cancer Therapy and Imaging
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To reduce the side effects of chemotherapy, nontoxic prodrugs activated by the tumor microenvironment are urgently required for use in cancer treatment. In this work, we developed prodrug 4 for tumor-targeting treatment and imaging of the anticancer drug release in vivo. Taking advantage of the high glutathione (GSH) concentration in cancer cells, the disulfide bond in prodrug 4 was cleaved, resulting in the release of an active anticancer drug and a near-infrared (NIR) fluorescence dye turn-on. Furthermore, contrast to the free anticancer drug, the prodrug exhibited higher cytotoxicity to hepatoma cells than that to normal HL-7702 cells. Thus, prodrug 4 is a promising platform for specific tumor-activatable drug delivery system, because of its favorable features of in situ and in vivo monitoring of the drug release and therapeutic efficacy.
- Kong, Fanpeng,Liang, Ziye,Luan, Dongrui,Liu, Xiaojun,Xu, Kehua,Tang, Bo
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p. 6450 - 6456
(2016/07/06)
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- Small molecular nanomedicines made from a camptothecin dimer containing a disulfide bond
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A small molecular camptothecin (CPT) dimer could self-assemble into stable nanoparticles in aqueous solution, which was characterized by TEM and DLS. These nanomedicines could be internalized by cancer cells as revealed by confocal laser scanning microscopy, and indicated high cellular proliferation inhibition toward HeLa and HepG2 cells with low IC50 values and reduction-responsive cytotoxicity towards HeLa cells. The feasible assembly method and outstanding properties of CPT-NPs provide an alternative approach for exploring new nanomedicines for cancer therapy.
- Pei, Qing,Hu, Xiuli,Li, Zhensheng,Xie, Zhigang,Jing, Xiabin
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p. 81499 - 81501
(2015/10/06)
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- Short protecting group-free syntheses of camptothecin and 10-hydroxycamptothecin using cascade methodologies
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A convergent protecting group-free total synthesis route of camptothecin and 10-hydroxycamptothecin has been developed in this work. Cascade oxidation of 3-(hydroxymethyl)furan-2(5 H)-one and in situ intermolecular oxa Diels-Alder reaction with vinyl ether was developed and applied to construct the E-ring, and TMSCl-promoted cascade closure of the D-ring delivered the whole skeleton of the alkaloids in the total synthesis. The new short syntheses were advantageous with regard to step economy, low cost, easily available starting materials and reagents, and convenient operations.
- Xu, Peng,Chen, Dong-Sheng,Xi, Jie,Yao, Zhu-Jun
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p. 976 - 981
(2015/04/14)
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- Linker-determined drug release mechanism of free camptothecin from self-assembling drug amphiphiles
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We report here that the release mechanism of free camptothecin from self-assembling drug amphiphiles can be regulated by use of different linker groups. Our results highlight the significance of the linker group of drug amphiphiles on the drug release efficiency and their consequent in vitro efficacy. the Partner Organisations 2014.
- Cheetham, Andrew G.,Ou, Yu-Chuan,Zhang, Pengcheng,Cui, Honggang
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p. 6039 - 6042
(2014/05/20)
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- Total synthesis of camptothecin and SN-38
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A new practical and concise total synthesis of enantiopure camptothecin and SN-38 (14% overall yield, 99.9% ee and 99.9% purity) was described, starting from inexpensive and readily available materials. The development of column chromatography-free purification was achieved in all steps, which offers an economic industrial process to the camptothecin-family alkaloids.
- Yu, Shanbao,Huang, Qing-Qing,Luo, Yu,Lu, Wei
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experimental part
p. 713 - 717
(2012/03/11)
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- Incorporation and controlled release of silyl ether prodrugs from PRINT nanoparticles
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Asymmetric bifunctional silyl ether (ABS) prodrugs of chemotherapeutics were synthesized and incorporated within 200 nm × 200 nm particles. ABS prodrugs of gemcitabine were selected as model compounds because of the difficulty to encapsulate a water-soluble drug within a hydrogel. The resulting drug delivery systems were degraded under acidic conditions and were found to release only the parent or active drug. Furthermore, changing the steric bulk of the alkyl substituents on the silicon atom could regulate the rate of drug release and, therefore, the intracellular toxicity of the gemcitabine-loaded particles. This yielded a family of novel nanoparticles that could be tuned to release drug over the course of hours, days, or months.
- Parrott, Matthew C.,Finniss, Mathew,Luft, J. Chris,Pandya, Ashish,Gullapalli, Anuradha,Napier, Mary E.,Desimone, Joseph M.
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supporting information; experimental part
p. 7978 - 7982
(2012/06/18)
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- A novel and enantioselective total synthesis of (20 S)-camptothecin via a Sharpless asymmetric dihydroxylation strategy
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A novel and efficient asymmetric total synthesis of (20S)-camptothecin has been accomplished in an overall yield of 12% starting from the commercially available 2-methoxynicotinic acid. The key step in the sequence is the Sharpless asymmetric dihydroxylation of a 4-(but-1-en-2-yl)pyridine derivative to establish the stereocenter of (20S)-camptothecin. Georg Thieme Verlag Stuttgart · New York.
- Zhao, Lei,Xiong, Fang-Jun,Chen, Wen-Xue,Chen, Fen-Er
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p. 4045 - 4049
(2012/01/19)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- Simultaneous determination of irinotecan hydrochloride and its related compounds by high performance liquid chromatography using ultraviolet detection
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A new simple, precise and accurate high performance liquid chromatography (HPLC) method was developed and validated for the simultaneous determination of irinotecan (CPT-11) and two related compounds viz., 7-ethyl-10-hydroxycamptothecin (SN-38) and camptothecin (CPT) in pharmaceutical dosage forms. Chromatography was accomplished using a reversed-phase C18 column and ultraviolet (UV) detection and an isocratic mobile phase consisting of 3% v/v triethylammonium acetate buffer (pH 3) and acetonitrile (70:30 v/v). The linear range of quantitation for all the compounds was 0.1-10 μg/mL. The limit of quantitation for all the compounds ranged between 0.01-0.05 μg/mL. The method has the requisite accuracy, selectivity, sensitivity and precision to assay of CPT-11 and related compounds in pharmaceutical dosage forms and bulk API.
- Mohammadi, Ali,Esmaeili, Farnaz,Dinarvand, Rassoul,Atyabi, Fatemeh,Walker, Roderick B.
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scheme or table
p. 3966 - 3972
(2010/11/18)
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- PROCESS FOR PRODUCTION OF CAMPTOTHECIN DERIVATIVE
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Disclosed is a process for production of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycampto thecin from a camptothecin composition containing 18,19-dehydrocamptothecin without producing any vinyl form of the compound. The process is characterized by catalytically reducing at least one compound selected from a compound (1) and others in the process of producing a compound (5) from a composition containing the compound (1).
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(2009/01/24)
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- Expeditious total syntheses of camptothecin and 10-hydroxycamptothecin
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(Chemical Equation Presented) New expeditious total syntheses of (S)-camptothecin (16% overall yield, 95% ee) and (S)-10-hydroxycamptothecin (14% overall yield, 99% ee) have been accomplished, respectively, starting from readily available and inexpensive materials. Development, optimization, and successful application of the cascade reaction consisting of a pyrrolidine-catalyzed Michael addition, an intramolecular aldol condensation, and an oxidative aromatization, the intramolecular oxa Diels-Alder cycloaddition, and the Sharpless asymmetric dihydroxylation make these two new syntheses more efficient and straightforward.
- Liu, Guan-Sai,Dong, Qing-Li,Yao, Yuan-Shan,Yao, Zhu-Jun
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supporting information; experimental part
p. 5393 - 5396
(2009/06/28)
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- New route to natural camptothecin through isomünchnone cycloaddition
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A novel approach to camptothecin by [3+2] cycloaddition of an isomünchnone intermediate is described. Georg Thieme Verlag Stuttgart.
- Kanazawa, Alice,Muniz, Mauro N.,Baumlová, Barbora,Ljungdahl, Natalie,Greene, Andrew E.
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body text
p. 2275 - 2278
(2009/05/27)
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- Highly efficient and mild cascade reactions triggered by bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate and a concise total synthesis of camptothecin
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A mild and efficient cascade methodology is reported to construct variously substituted indolizino[1,2-b]quinolin-9(11H)-ones. Efficiently triggered by bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate under mild conditions, this cascade achieved significant enhancements in chemical yields. Utilizing this highly efficient domino reaction followed by a Sharpless dihydroxylation, an eight-step total synthesis of camptothecln was accomplished from a known pyridine derivative in direct fashion with an overall yield of 47% and 95% ee.
- Zhou, Hai-Bin,Liu, Guan-Sai,Yao, Zhu-Jun
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p. 2003 - 2005
(2008/02/02)
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- PROCESS FOR PREPARING TOPOTECAN
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A process for preparing topotecan.
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(2008/06/13)
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- Camptothecin derivatives and improved synthetic methods
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The present invention relates to compositions and methods for preparing pharmaceutical compositions. In some embodiments, the invention includes compounds and methods of resolving chiral compounds. In some embodiments, the invention includes chiral and crystalline compositions and hydrates. In some embodiments, the invention contemplates compositions comprising camptothecin derivatives and synthetic intermediates thereof. In some embodiments, the invention includes methods of protecting, inserting, modifying, separating isomers, and removing chemical groups.
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(2008/06/13)
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- Total synthesis of (+)-camptothecin via an intramolecular palladium-catalyzed cyclization strategy
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The novel cascade intramolecular Pd-catalyzed cyclization followed by aromatization for the construction of D ring of (+)-camptothecin as a key step is demonstrated. Georg Thieme Verlag Stuttgart.
- Chavan, Subhash P.,Pathak, Ashok B.,Kalkote, Uttam R.
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p. 2635 - 2638
(2008/02/12)
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- Novel, efficient total synthesis of natural 20(S)-camptothecin
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A modular approach to racemic and achiral camptothecinoids from the Padwa hydroxypridone which is based in part on a Claisen rearrangement and a Friedlander condensation was analyzed. The elements necessary for the construction of the chiral hydroxyl lactone derivative would be introduced by a Claisen rearrangement for the β substituent and a Heck coupling for the α substituent. Hydroxypyridone 3 was obtained in high yield from 2 pyrrolidinone and then converted into crotonate 4 in 96% yield through reaction with methyl 4 bromocrotonate. To cleave oxidatively the ethylidene group in 5a, it proved necessary to first deactivate the hydroxypyridone moiety by triflation and this permitted the desired scission to proceed selectively with ozone in dichloromethane to give keto ester 6 in 96% yield. Result shows that a new synthesis of 20 (S)-camptothecin has been developed which is both efficient and flexible.
- Tang, Chao-Jun,Babjak, Matej,Anderson, Regan J.,Greene, Andrew E.,Kanazawa, Alice
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p. 3757 - 3759
(2008/09/18)
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- DUAL PHASE DRUG RELEASE SYSTEM
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The present invention relates to conjugate comprising a carrier substituted with one or more occurrences of a moiety having the structure (I): wherein each occurrence of M is independently a modifier having a molecular weight ≤ 10 kDa; denotes direct of indirect attachment of M to linker LM; and each occurrence of LM is independently an optionally substituted succinamide-containing linker, whereby the modifier M is directly or indirectly attached to the succinamide linker through an amide bond, and the carrier is linked directly or indirectly to each occurrence of the succinamide linker through an ester bond. In another aspect, the invention provides compositions comprising the conjugates, methods for their preparation, and methods of use thereof in the treatment of various disorder, including, but not limited to cancer.
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(2008/06/13)
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- Process for making camptothecin derivatives
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A process for synthesizing highly lipophilic derivatives of camptothecin. The process includes reacting dissolved, underivatized camptothecin with an aldehyde in a modified Minisci-type alkylation reaction to produce 7-substituted derivatives of camptothecin.
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- Special preparation of anticancer drugs made by novel nanotechnology
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The present invention relates to a new technique formed from polysaccharides of kelp (PK), which has function of anticancer and increasing immunity, and new nanoparticles (NP) and special liposome (SSL), which contained natural anticancer drug their preparation. Also, the present invention is aimed at the overall improvement of therapeutic efficacy of anticancer drugs, including Homoharringtonine (HHT), Curcumol (CUR), Eelemene (ELE) and Camptothecin (CPT) by NP and SSL. NP improves the anticancer therapeutic efficacy of HHT, CUR, ELE and CPT by using PK as polymer. PK can improve the anticancer therapeutic index and decrease side effect of free anticancer drugs. Also, PK has the function of increasing immunity. The present invention disclosed a process for making a polysaccharide of kelp (PK), PK-Drug-NP and special PK-anticancer drug-containing sterically stabilized liposomes (PK-Drug-SSL).
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- PROCESS FOR PRODUCING CAMPTOTHECIN
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Problem: A large scale production of camptothecin, which is a starting compound of irinotecan hydrochloride and various camptothecin derivatives, at a low cost and with ease. Solution: A process for preparing camptothecin, characterized in that it comprises the following steps (a) and (b);(a) the step to hydrolyze 9-methoxycamptothecin or a natural material containing 9-methoxycamptothecin;(b) the step to convert 9-hydroxycamptothecin obtained in the step (a) into camptothecin by 9-O-perfluoro-lower-alkylsulfonylation or 9-O-phenyltetrazolylation, followed by hydrogenolysis.
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- Method for identifying an enzyme to design anti-cancer compounds
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The present invention relates to a method for identification of enzymes that are preferentially expressed in certain tumor tissue as compared with rapidly growing normal cells or tissue, use of said enzymes for the compound design to generate an active anti-cancer substance selectively in tumor tissue, compounds designed based on said enzymes, their pharmaceutically acceptable salts as well as pharmaceutical composition thereof.
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- Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: Total synthesis of (±)-20-deoxycamptothecin and (+)-camptothecin
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Several 4-substituted dihydropyridones or 2-pyridones have been prepared by nucleophilic addition of α-(methylsulfanyl)ester enolates to N-alkyl-2-fluoropyridinium salts, followed by acid hydrolysis or oxidation with concomitant hydrolysis, of the intermediate 2-fluoro-1,4-dihydropyridine adducts, respectively. Addition of the enolate derived from isopropyl α-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoropyridinium triflate 21 followed by DDQ treatment gave pyridone 29, from which (±)-20-deoxycamptothecin (31), a known precursor of camptothecin, was synthesized by a radical cyclization-desulfurization, with subsequent elaboration of the lactone E ring by chemoselective reduction. A similar sequence starting from the enolate of a chiral 2-hydroxybutyric acid derivative (33) provides access to natural (+)-camptothecin (37).
- Bennasar, M.-Lluisa,Zulaica, Ester,Juan, Cecilia,Alonso, Yolanda,Bosch, Joan
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p. 7465 - 7474
(2007/10/03)
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- Antiangiogenic combination therapy for the treatment of cancer
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The present invention provides combinations of a DNA topoisomerase I inhibiting agent and a selective COX-2 inhibiting agent for preventing, treating, and/or reducing the risk of developing a neoplasia disorder in a mammal.
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- Terminally-branched polymeric linkers and polymeric conjugates containing the same
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The present invention is directed to polymeric-prodrug transport forms of the formula: wherein: E1-4are independently selected from the group consisting of hydrogen, C1-6alkyls, C3-12branched alkyls, C3-8cycloalkyls, C1-6substituted alkyls, C3-8substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6heteroalkyls, substituted C1-6heteroalkyls, C1-6alkoxy, phenoxy, C1-6heteroalkoxy, and at least one of E1-4includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl-or amino-containing moiety or wherein J1is the same as J, or another member of the group defining J and E5is the same as E1-4, or another member of the group defining E1-4; Y1-2are independently O, S or NR9; M is a heteroatom selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(=Y2); R2-5and R7-9are independently selected from the group consisting of hydrogen, C1-6alkyls, C3-12branched alkyls, C3-8cycloalkyls, C1-6substituted alkyls, C3-8substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-16heteroalkyls, substituted C1-6heteroalkyls, C1-6alkoxy, phenoxy and C1-6heteroalkoxy; (m1) and (m2) are independently zero or one; (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer, Z is an electron withdrawing group; and R1is a polymeric residue. which is optionally capped with a moiety of the formula:
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- Synthesis of silyl camptothecins and silyl homocamptothecins
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A method of synthesizing 7-silyl camptothecins and 7-silyl homocamptothecins includes the step of mixing a camptothecin or a homocamptothecin having hydrogen at the C7 position with a silyl radical generator and a silyl radical precursor under conditions to generate a silyl radical. SiR1R2R3wherein R1, R2and R3are independently a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, an aryl group, —(CH2)mR11or SiR12R13R14, wherein m is an integer within the range of 1 through 10 and R11is a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, F, Cl, a cyano group, —SRcor a nitro group, and wherein R12, R13and R14are independently the same or different an alkyl group or an aryl group.
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- Total synthesis of (+)-camptothecin
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A total synthesis of (+)-camptothecin is described. The approach is based on a room temperature LUMOdiene-controlled Diels-Alder cycloaddition of the electron deficient N-sulfonyl-1-aza-1,3-butadiene 6 with the electron rich dienophile 1,1,3,3-tetraethoxypropene (7) for assembly of a pyridine precursor to the D-ring pyridone. The 20(S) tertiary alcohol was installed through a Sharpless asymmetric dihydroxylation reaction on the methyl vinyl ether 12, using the 3,4,5-trimethoxyphenyl-derived pyrimidine DHQ dimer ligand 16. In a single reaction vessel, the C and E rings were closed using an acid-catalyzed deprotection of the benzylic ethers to afford the corresponding benzylic bromides (18) which underwent intramolecular nucleophilic displacement by the carboxylate and pyridone nitrogen to furnish (+)-camptothecin.
- Blagg, Brian S.J.,Boger, Dale L.
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p. 6343 - 6349
(2007/10/03)
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- A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs
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We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR ω-aminoalkanoanic ester prodrug in which R = CO[CH2]nNH2 and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group). Copyright
- Liu, Xinli,Lynn, Bert C.,Zhang, Junhong,Song, Lin,Bom, David,Du, Wu,Curran, Dennis P.,Burke, Thomas G.
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p. 7650 - 7651
(2007/10/03)
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- Intermediates in the synthesis of camptothecin and related compounds and synthesis thereof
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The present invention provides a short, convergent total synthesis of irinotecan and derivative compounds which comprises of a novel 4+1 radical annulation wherein the precursor is reacted with an aryl isonitrile having the formula wherein X is Br or I, and R4is an alkyl group, an allyl group, a propargyl group or a benzyl group, and R16is H, a C1-C6alkoxy group, a group wherein p is an integer between 4 and 12, or a C1-C12acyclic dialkylamino group. The present invention also provides novel chemical intermediates for such 4+1 radical annulations.
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- Polymeric derivatives of camptothecins
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The invention relates to polymeric conjugates of 20-O-[glycyl-aminoacyl-glycyl]-camptothecins and a process for producing the same.
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- Sugar-modified cytostatics
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The invention relates to cytostatics which, by modification with sugar, are tumor-specific. Suitable spacers ensure serum stability and at the same time an intracellular action.
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- Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs
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Liposomal prodrugs include specific derivatives of camptothecin restrained by a liposomal delivery system. The derivatives of camptothecin are represented by the general formula: wherein when R2 is H, R1 is a C2-C4 alkyl group, a C6-C15 alkyl group, a C3-C8 cycloalkyl group, a C2-C15 alkenyl group or a C2-C15 epoxy group; and when R2 is a nitro group, R1 is a C1-C15 alkyl group, a C2-C15 alkenyl group, a C3-C8 cycloalkyl group, or an epoxy group. Processes for making these prodrugs and for using them in cancer treatment are also disclosed.
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