Aminocamptothecin - CAS 91421-43-1
Catalog number: 91421-43-1
Category: Inhibitor
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Molecular Formula:
C20H17N3O4
Molecular Weight:
363.373
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Description:
Aminocamptothecin is a water-insoluble camptothecin derivative. Aminocamptothecin binds to the nuclear enzyme topoisomerase I, thereby inhibiting repair of single-strand DNA breakages.
Synonyms:
9-aminocamptothecin; 9-amino-camptothecin; 9-amino-CPT; 9-AC; 9-amino-20(S)-camptothecin; 9-amino-20-camptothecin.
MSDS:
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InChIKey:
FUXVKZWTXQUGMW-FQEVSTJZSA-N
InChI:
InChI=1S/C20H17N3O4/c1-2-20(26)13-7-16-17-10(6-11-14(21)4-3-5-15(11)22-17)8-23(16)18(24)12(13)9-27-19(20)25/h3-7,26H,2,8-9,21H2,1H3/t20-/m0/s1
Canonical SMILES:
CCC1(C2=C(COC1=O)C(=O)N3CC4=C(C3=C2)N=C5C=CC=C(C5=C4)N)O
1.Physicochemical characterization of 9-aminocamptothecin in aqueous solutions.
Rahman S1, Patel D, Savva M. AAPS PharmSciTech. 2014 Feb;15(1):223-9. doi: 10.1208/s12249-013-0046-y. Epub 2013 Dec 3.
The present manuscript provides a detailed physicochemical and thermodynamic characterization of 9-aminocamptothecin (9AC) which can be used as a tool to develop novel formulation strategies for optimum pharmacological activity. The pKa of 9AC was determined to be 2.43 at 37°C, while the basicity of quinoline nitrogen of 9AC was found to decrease with increasing temperature due to a positive enthalpy of deprotonation of 10.36 kJ mol(-1). The equilibrium solubility as well as the intrinsic solubility of the drug was found to increase with increasing temperature and decreasing pH. The enthalpies of solution of unionized and ionized forms of 9AC obtained from isothermal and iso-pH equilibrium solubility measurements were found to be 36.01 and 24.72 kJ mol(-1), respectively. Equilibrium hydrolysis studies revealed the hydrolytic susceptibility of 9AC with only 14% of active lactone species remaining at physiological pH 7.4. The intrinsic partition coefficient log P of the free base, 9AC-lactone, was estimated to be 1.
2.Antitumor efficacy of colon-specific HPMA copolymer/9-aminocamptothecin conjugates in mice bearing human-colon carcinoma xenografts.
Gao SQ1, Sun Y, Kopecková P, Peterson CM, Kopecek J. Macromol Biosci. 2009 Nov 10;9(11):1135-42. doi: 10.1002/mabi.200900147.
The antitumor activity of a colon-specific N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer - 9-aminocamptothecin (9-AC) conjugate (P-9-AC) was assessed in orthotopic and subcutaneous animal (HT29 xenograft) tumor models. P-9-AC treatment of mice bearing orthotopic colon tumors, with a dose of 3 mg/kg of 9-AC equivalent every other day for 6 weeks, resulted in regression of tumors in 9 of 10 mice. A lower dose of P-9-AC (1.25 mg/kg of 9-AC equivalent) every other day for 8 weeks inhibited subcutaneous tumor growth in all mice. No liver metastases were observed. Colon-specific release of 9-AC from polymer conjugates enhanced antitumor activity and minimized the systemic toxicity.
3.Kinetic and thermodynamic studies of 9-aminocamptothecin hydrolysis at physiological pH in the presence of human serum albumin.
Patel D1, Rahman S, Savva M. Eur J Pharm Sci. 2013 Aug 16;49(5):858-63. doi: 10.1016/j.ejps.2013.06.005. Epub 2013 Jun 19.
As a first step towards improving the aqueous stability of 9-aminocamptothecin (9AC), a detailed kinetic and thermodynamic investigation of the hydrolysis reaction of 9AC was carried out, using a first derivative absorption spectrophotometry technique. It was found that 9AC-lactone decayed with a half-life of 25 min in PBS at pH 7.4 and 310.15K. The activation energy (Ea) associated with the hydrolysis of 9AC-lactone was 87.3 ± 3.8 kJmol(-1), whereas the positive enthalpy and entropy values of the 9AC-lactone hydrolysis reaction indicated that the reaction is endothermic and entropically driven. Similarly to other camptothecin analogs, except for SN38, the activation energy for 9AC-lactone hydrolysis in the presence of Human Serum Albumin (HSA) was about 10 kJmol(-1) lower than that determined in plain PBS, whereas the equilibrium 9AC-lactone concentration was decreased in the presence of HSA as compared to that in plain PBS. The lower Ea for 9AC hydrolysis in presence of HSA fully explained the shift of lactone-carboxylate equilibrium towards the carboxylate form with only 4% of active 9AC-lactone remaining in the presence of HSA under physiological conditions.
4.Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines.
Hamilton G1, Klameth L2, Rath B3, Thalhammer T4. Molecules. 2014 Feb 17;19(2):2077-88. doi: 10.3390/molecules19022077.
Advanced small cell lung cancer (SCLC) has a dismal prognosis. Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our recent finding of synergistic enhancement of the cytotoxic activity of camptothecin (CPT) by cyclin-dependent kinase 4 inhibitors is extended here to a panel of camptothecin analogs comprising 10-hydroxy-CPT (HOCPT), topotecan (TPT; 9-[(dimethylamino)-methyl]-10-hydroxy-CPT), 9-amino-CPT (9AC), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin) and 10-hydroxy-9-nitrocamptothecin (CPT109) in combination with PD0332991, CDK4I, roscovitine and olomoucine. SCLC cell lines employed are chemoresistant NCI-H417 and DMS153 and the chemosensitive SCLC26A line established at our institution. The CPT analogs exhibiting highest cytotoxicity towards the three SCLC lines tested were SN38 and 9AC, followed by rubitecan, HOCPT, TPT and CPT109. NCI-H417 and DMS153 revealed an approximately 25-fold and 7-fold higher resistance compared to the chemosensitive SCLC26A cell line.
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CAS 91421-43-1 Aminocamptothecin

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