- 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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- 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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Read Online
- Synthesis of 10-hydroxycamptothecin: Evaluation of new moderators for the chemoselective reduction of camptothecin
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10-Hydroxycamptothecin is prepared by chemoselective catalytic hydrogenation of the B-ring of camptothecin over PtO2 with sulfur moderators followed by oxidation using iodobenzenediacetate. New moderators (viz. thioanisole, dimethyl sulfide, diphenyl sulfide, 2-mercapto ethanol), which moderate the hydrogenation of the B- ring of camptothecin, are being explored. Dr. Reddy's Laboratories Ltd.
- Sekhar,Anjaneyulu, Yerramilli,Acharyulu, V.R.Palle
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Read Online
- Multi-gram scale synthesis of a bleomycin (BLM) carbohydrate moiety: exploring the antitumor beneficial effect of BLM disaccharide attached to 10-hydroxycamptothecine (10-HCPT)
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The “tumor-seeking” role of bleomycin (BLM) disaccharide has been demonstrated to serve as a promising tool for cancer diagnosis and a potential ligand for targeted therapy. However, these practical applications are often hampered by the lack of BLM disaccharide. Herein, an efficient multi-gram synthesis of peracetylated BLM disaccharide 20 is achieved by a TMSOTF-mediated glycosidation coupling manner in 43.6% overall yield in terms of benzyl galactoside. The critical innovation of the synthetic strategy is that inexpensive benzyl galactoside was first adopted to prepare an l-gulose subunit 3 as a glycosyl acceptor, with a much shorter route in 73.0% yield, and a 3-O-carbamoyl-mannose donor 4 was achieved in 47.2% yield by lowering the amount of dibutyltin oxide, and merging aminolysis and selective deacetylation into a one-pot reaction. Next, the incorporation of BLM disaccharide into 10-hydroxycamptothecin (10-HCPT), a non-specific model compound, to form conjugate 1 could significantly improve the antitumor activity and display obvious selectivity toward cancerous and normal cells in comparison with 10-HCPT. Moreover, BLM disaccharide itself was non-cytotoxic, clearly indicating the importance and potential of BLM disaccharide in solving the targeted antitumor therapy of cytotoxic drugs.
- Li, MaoLin,Huang, Weiping,Jiang, Zhilin,Shi, Yonghui,Yuan, Sisi,Fu, Kaishuo,Chen, YongJun,Zhou, Li,Zhou, Wen
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p. 6010 - 6020
(2019/04/17)
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- Chemical semi-synthesis process of 10-hydroxycamptothecine
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The invention discloses a chemical semi-synthesis process of 10-hydroxycamptothecine. The chemical semi-synthesis process is characterized in that 20(S)-camptothecin, which is used as the raw material, is subjected to optimized N-oxidation and photochemical rearrangement reaction, and the product is subjected to silica gel column chromatography, so that high-purity 10-hydroxycamptothecine can be obtained. The chemical semi-synthesis process is simple and convenient in process conditions, the reaction reagent can be recycled, the production cost is low, the yield of 10-hydroxycamptothecine products is high, and the product is liable to separation, and accords with the national drug testing standard with the purity of 98.5%.
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Paragraph 0006; 0007
(2016/10/10)
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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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p. 713 - 717
(2012/03/11)
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- Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy
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A β-glucuronidase-activated prodrug approach was applied to 10-hydroxycamptothecin, a Camptotheca alkaloid with promising antitumor activity but poor water solubility. We synthesized a glucuronide prodrug of 10-hydroxycamptothecin (7) in which glucuronic acid is connected via a self-immolative 3-nitrobenzyl ether linker to the 10-OH group of 10-hydroxycamptothecin. Compound 7 was 80 times more soluble than 10-hydroxycamptothecin in aqueous solution at pH 4.0 and was stable in human plasma. Prodrug 7 was 10-to 15-fold less toxic than the parent drug to four human tumor cell lines. In the presence of β-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli β-glucuronidase had a quite low Km of 0.18 μM for compound 7 and exhibited 520 times higher catalytic efficiency for 7 than for 6 (a glucuronide prodrug of 9-aminocamptothecin). Molecular modeling studies predicted that compound 7 would have a higher binding affinity to human β-glucuronidase than compound 6. Prodrug 7 may be useful for selective cancer chemotherapy by a prodrug monotherapy (PMT) or antibody-directed enzyme prodrug therapy (ADEPT) strategy.
- Leu, Yu-Ling,Chen, Chien-Shu,Wu, Yih-Jang,Chern, Ji-Wang
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p. 1740 - 1746
(2008/09/21)
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- PROCESS FOR PREPARING IRINOTECAN
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The present invention relates to a process for the preparation of pure irinotecan or salts thereof, and a process for the preparation of intermediate compound 7-ethyl-10-hydroxycamptothecin.
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Page/Page column 6-7
(2008/06/13)
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- PROCESS FOR PREPARING TOPOTECAN
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A process for preparing topotecan.
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Page/Page column title page; 7
(2008/06/13)
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- A practical regiospecific synthesis of 9-nitrocamptothecin
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9-Nitrocamptothecin has shown potent antitumor activity against many types of human cancers. A practical scale-up procedure for this compound is reported by selective reduction of corresponding sulfonate. Georg Thieme Verlag Stuttgart.
- Fu, Qingquan,Chen, Zhiyong
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p. 1940 - 1942
(2007/10/03)
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- Process to prepare camptothecin derivatives and novel intermediate and compounds thereof
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New processes are disclosed for the preparation of camptothecin derivatives, such as, irinotecan and topotecan, as well as new intermediates and compounds related thereof.
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Page/Page column 13; 3/8
(2008/06/13)
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- Radiosynthesis of carbon-11-labeled camptothecin derivatives as potential positron emission tomography tracers for imaging of topoisomerase I in cancers
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Four carbon-11-labeled camptothecin derivatives, 9-[11C]methoxy- 20(S)-camptothecin ([11C]5), 10-[11C]methoxy-20(S)- camptothecin ([11C]7), 9-nitro-10-[11C]methoxy-20(S)- camptothecin ([11C]9), and 9-[([11C]trimethylamino)methyl] -10-hydroxy-20(S)-camptothecin ([11C]11), have been synthesized as potential positron emission tomography tracers for imaging of topoisomerase I in cancers.
- Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
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p. 3865 - 3869
(2007/10/03)
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- PROCESS FOR PREPARING TOPOTECAN FROM 10-HYDROXY-4-(S) CAMPTOTHECIN
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The present invention relates to the use of dihalomethanes as reagents for the preparation of Topotecan {4-(S)-10 (dimethylamino)-methyl-4-ethyl 4, 9 dihydroxyl-H-pyrano [3'4': 6,7] indolizino-[1,2-b]quinoline-3,14 (4H,12H)dione} from 10-hydroxycamptothecin. The invention discloses the rationale use of dichloromethane under solid-liquid phase transfer catalysis, which can behave both as solvent and a reactant when it serves as a source for C-1 unit for amino-alkylation of 10-hydroxy-4-(S) camptothecin.
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- Process for preparing Topotecan from 10-hydroxy-4-(S) camptothecin
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The present invention relates to the use of dihalomethanes as reagents for the preparation of Topotecan{4-(S)-10(dimethylamino)-methyl-4-ethyl 4,9 dihydroxyl-H-pyrano[3′4′:6,7]indolizino-[1,2-b]quinoline-3,14(4H,12H)dione} from 10-hydroxycamptothecin. The invention discloses the rationale use of dichloromethane under solid-liquid phase transfer catalysis, which can behave both as solvent and a reactant when it serves as a source for C-1 unit for amino-alkylation of 10-hydroxy-4-(S)camptothecin.
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Page column 4, 5
(2008/06/13)
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- A general synthetic approach to the (20s)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cyclization of aryl isonitriles
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A general and efficient synthesis of (20S)-camptothecin (1a) is reported. A key common intermediate containing the pyridone and lactone (DE) rings of camptothecin and most derivatives was constructed from 2-trimethylsilyl-6-methoxypyridine by a series of metalation reactions and a Heck cyclization to provide an achiral bicyclic enol ether. Sharpless asymmetric dihydroxylation followed by lactol oxidation and iododesilylation produced the key intermediate in 94% enantiomeric excess. Alkylation with prop-argyl bromide and a cascade radical reaction with phenyl isonitrile then produced 1a. About 20 other penta-and hexacyclic analogues of camptothecin with differing single or multiple substituents at C7, C9, C10, C11, and/or C12 were made by changing the propargylating agent and the isonitrile. Included among these are several drug candidates and the approved drugs topotecan and irinotecan. The synthesis of the prodrug irinotecan is a direct one that does not pass through the active metabolite. The use of ortho-trimethylsilyl-substituted isonitriles allows the regioselective synthesis of camptothecin analogues in cases where isomeric mixtures are formed from the parent isonitriles. The synthesis of the derivatives relies on the broad scope and functional group tolerance of the key cascade radical reaction.
- Josien, Hubert,Ko, Sung-Bo,Bom, David,Curran, Dennis P.
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- Novel syntheses of camptothecin alkaloids. Part 2. Concise synthesis of (S)-camptothecins
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A 9-step, convergent total synthesis of (S)-camptothecin alkaloids is described. The intramolecular [4 + 2] cycloaddition of an N-arylimidate with an alkyne is used to prepare the alkaloid ABC ring system. The chiral center is derived utilizing Seebach's chemistry for the diastereoselective Michael addition of a chiral dioxolanone enolate to a methylene malonate acceptor. The total synthesis of non-racemic topotecan is accomplished from (S)-10-hydroxycamptothecin in an additional step.
- Fortunak, Joseph M.D.,Kitteringham, John,Mastrocola, Antonietta R.,Mellinger, Mark,Sisti, Nicolas J.,Wood, Jeffery L.,Zhuang, Zhi-Ping
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p. 5683 - 5686
(2007/10/03)
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- A new high yield semisynthetic approach to (20S)-9-NH2-Camptothecin based on a sequence of palladium-catalysed reductions
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A new 5-step synthesis of 9-NH2-Camptothecin starting from natural Camptothecin is described. The approach, centred on a double palladium catalysed reduction of an arylsulfonate and a nitro group, has an overall yield consistently higher than the previously reported ones.
- Cabri, Walter,Candiani, Ilaria,Zarini, Franco,Penco, Sergio,Bedeschi, Angelo
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p. 9197 - 9200
(2007/10/02)
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- 11,7 substituted camptothecin derivatives and formulations of 11,7 substituted camptothecin derivatives and methods for uses thereof
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The novel compounds 11-hydroxy-7-ethyl camptothecin and 11-hydroxy-7-methoxy camptothecin (11,7-HECPT and 11,7-HMCPT) are active anticancer compounds which are poorly soluble in water. Because of their novelty, 11,7-HECPT and 11,7-HMCPT derivatives have not been directly administered by parenteral or oral routes to human subjects as an antitumor composition for the purpose of inhibiting the growth of cancer cells. The claimed compositions are useful as compared to the water soluble camptothecin derivatives, such as CPT-11, in clinical trials. The unpredictable interpatient variability in the metabolic production of an active metabolite from CPT-11 limits the utility of CPT-11. This invention overcomes these limitations by claiming novel pharmaceutically acceptable lactone stable formulations of 11,7-HECPT or 11,7-HMCPT, to directly administer to patients. The present invention also claims 11,7-HECPT and 11,7-HMCPT compositions, the synthesis of 11,7-HECPT or 11,7-HMCPT, the methods of formulation of 11,7-HECPT or 11,7-HMCPT, and the methods of use of 11,7-HECPT or 11,7-HMCPT. Additionally, the claimed invention is directed to novel dosages, schedules, and routes of administration for both the 11,7-HECPT or 11,7-HMCPT formulations to humans with various forms of cancer. Other embodiments of this invention include isolation methods and methods of synthesis of certain camptothecin derivatives.
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- Kaskaden-Radikalreaktionen von Isocyaniden: eine zweite Generation der Synthese von (20S)-Camtothecin, Topotecan, Irinotecan und G1-147211C
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Keywords: Camptothecin; Isocyanide; Kaskadenreaktionen; Radikale
- Curran, Dennis P.,Ko, Sung-Bo,Josien, Hubert
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p. 2948 - 2950
(2007/10/03)
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- Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins
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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.
- Sawada,Matsuoka,Nokata,Nagata,Furuta,Yokokura,Miyasaka
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p. 3183 - 3188
(2007/10/02)
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- Synthesis of water-soluble (aminoalkyl)camptothecin analogues: Inhibition of topoisomerase I and antitumor activity
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Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxy-camptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25, 26) or by total synthesis (35, 42, 43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK and F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.
- Kingsburgy,Boehm,Jakas,Holden,Hecht,Gallagher,Caranfa,McCabe,Faucette,Johnson,Hertzberg
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