nach oben

Drugs in R&D

Erschienen in:

01.11.2007 | Original Research Article

Alkylation Activity and Molecular Properties of Two Antineoplastic Agents that Utilise Indometacin and a Conjugate of Aspirin with 2-Aminonicotinic Acid to Transport Nitrogen Mustard Groups

verfasst von: Dr Ronald Bartzatt

Erschienen in: Drugs in R&D | Ausgabe 6/2007

Einloggen, um Zugang zu erhalten

Abstract

Background: Nitrogen mustard (N-mustard) compounds are considered important anticancer drugs. Various transporting agents have been utilised to carry Nmustard groups including coumarins, amides, polyaromatic molecules and cycloalkyl structures. N-mustards act as bifunctional alkylating agents that induce cross-linking within DNA strands and cytotoxic activity. Compounds that transport the N-mustard group in vivo can also express drug-likeness that can have advantages in clinical application. This study presents data on two anticancer drugs with N-mustard groups covalently attached to NSAIDs.

Methods: Two alkylating compounds were synthesised by covalently attaching a single N-mustard group to 2-2-acetoxybenzoylaminonicotinic acid (for compound I) and indometacin (for compound II). Molecular properties such as aqueous solubility, 1-octanol/water partitioning coefficient (log Kow), molar volume, polar surface area, 1-octanol/water partitioning at pH values other than human blood (log D) and the dermal permeability coefficient (Kp) were determined. The rate-order of reaction and rate constant of alkylation were determined by reacting compound I and compound II with a target compound having a primary amine group in buffered aqueous solution at blood pH 7.4 and 37°C, and monitoring absorbance at 400nm.

Results and conclusion: Compounds I and II were stable at room temperature, soluble in water and effectively alkylated a nucleophilic primary amine target at physiological temperature and pH. The water solubility of compound I was considerably greater than that of compound II. Both compounds showed second-order rate order of alkylation and effectively alkylated a nucleophilic target under aqueous physiological conditions of pH 7.4 and 37°C. Kp values for compounds I and II were determined to be 0.000786 cm/h and 0.024 cm/h, respectively. Both compound I and compound II had zero percent ionisation at pH 7.4, and compound I showed zero violations of the Rule of 5. Log P values for compounds I and II were 3.27 and 5.08, respectively. This study describes the benefits of antineoplastic agents with NSAID substituents that provide favourable pharmacological properties.

Nogrady T. Medicinal chemistry. New York: Oxford University Press, 1988

Gringauz A. Medicinal chemistry. New York: Wiley-VCH, 1997

Mattes W, Hartley J, Kohn K. DNA sequence selectivity of guanine N-7 alkylation by nitrogen mustards. Nucl Acids Res 1986; 14 (7): 2971–87PubMedCrossRef

Workman P. Inhibition of human prostatic tumor acid phosphatase by N,N-p-di-2-chloroethylaminophenol, N,N-p-di-2-chloroethylaminophenyl phosphate and other difunctional nitrogen mustards. Chem Biol Interact 1978; 20 (1): 103–12PubMedCrossRef

Peiper R, Erickson L. DNA adenine adducts induced by nitrogen mustards and their role in transcription termination in vitro. Carcinogenesis 1990; 11: 1739–46CrossRef

Burchenal J, Burchenal JR, Johnston S. Chemotherapy of leukemia: III. Further studies on the effect of nitrogen mustards and related compounds on transmitted mouse leukemia. Cancer 1951; 4: 353–6PubMedCrossRef

Sulik R. Treatment of malignancies of the lymphoid and reticular systems by a new nitrogen mustard derivative. Arzneimitlar systems by a new nitrogen mustard derivative. Arzneimittel Forschung 1958; 8: 360–1

Sampey J. Nitrogen mustards in the management of Hodgkin’s disease and the leukemias. J S C Med Assoc 1963; 59: 272–4PubMed

Pop F, Roth S, Kirby J. Synthesis of potential anticancer agents: IX. Some cycloalkyl mustards and related compounds. J Med Chem 1963; 6: 83–6CrossRef

10.

Elderfield R, Roy J. Synthesis of potential anticancer agents: XVII. Nitrogen mustards from 6-substituted coumarins. J Med Chem 1967; 10 (5): 918–21PubMedCrossRef

11.

Keitel R, Poege A. Testing of some nitrogen mustard compounds for cytostatic activity by a screening test. Archiv Fuer Geschwulstforschung 1975; 43 (2): 168–71

12.

Mathur I, Gupta H, Gupta SK. Antitumor activity of certain N-arylmethyl nitrogen mustards in Walker carcinosarcoma 256 and lymphocytic leukemia P 388. Indian Vet Med J 1977; 1 (1): 11–9

13.

Bacherikov V, Chou T, Dong H, et al. Potent antitumor N-mustard derivatives of 9-anilinoacridine, synthesis, and antitumor evaluation. Bioorg Med Chem Lett 2001 Sep; 14 (18): 4719–22CrossRef

14.

Conners T, Jenney A, Warwick G, et al. Factors influencing the sensitivity of tumors to nitrogen mustards. Isotop Exp Pharmacol 1965; 438

15.

Sun D, Hurley L. Analysis of the monoalkylation and cross-linking sequence specificity of bizelesin, a bifunctional alkylation agent related to (+)-CC-1065. J Am Chem Soc 1993; 115 (14): 5925–33CrossRef

16.

Paz M, Sigurdsson S, Hopkins P. Monoalkylation of DNA by reductively activated FR66979. Bioorg Med Chem 2000; 8 (1): 173–9PubMedCrossRef

17.

Palom Y, Kumar G, Tang LQ, et al. Relative toxicities of DNA cross-links and monoadducts: new insights from studies of decarbamoyl mitomycin C and mitomycin C. Chem Res Toxicol 2002; 15 (11): 1398–406PubMedCrossRef

18.

Osborne R, Lawley P. Alkylation of DNA by melphalan with special reference to adenine derivatives and adenine-guanine crosslinking. Chem Biol Interact 1993; 89 (10): 49–60PubMedCrossRef

19.

Kim Y, Martinez G, Varghese A, et al. Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience. Arch Dermatol 2003; 139 (2): 165–73PubMedCrossRef

20.

Chinn D, Chow S, Kim Y, et al. Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol 1999; 43 (5): 951–8CrossRef

21.

Ventafridda V, De Conno F, Peneral A, et al. Non-steroidal anti-inflammatory drugs as the first step in cancer pain therapy: double-blind, within-patient study comparing nine drugs. J Int Med Res 1990; 18 (1): 21–9PubMed

22.

Ding, X, Tong W, et al. Blockade of cyclooxygenase-2 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Anticancer Res 2000; 20 (4): 2625–31PubMed

23.

Morgan G, Vainio H. Non-steroidal anti-inflammatory drugs and cancer prevention: a review of the recent evidence. Curr Top Pharmacol 2002; 6: 25–39

24.

Gardiner P, Gillmer J. The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs. Mini-Rev Med Chem 2003; 3 (5): 461–70PubMedCrossRef

25.

Lupulescu A. Prostaglandins: their inhibitors and cancer. Prostaglandins Leukot Essent Fatty Acids 1996; 54 (2): 83–94PubMedCrossRef

26.

Greenberg E, Baron J, Freeman D, et al. Reduced risk of large-bowel adenomas among aspirin users. The Polyp Prevention Study Group. J Natl Cancer Inst 1993; 85 (11): 912–6PubMedCrossRef

27.

Goeke M. COX-2 independent antiproliferation action of acetyl-salicylic acid in human colon cancer cells. Eur J Clin Invest 2002; 32 (11): 793–4CrossRef

28.

Hull M, Gardner S, Hawcroft G. Activity of the non-steroidal anti-inflammatory drug indomethacin against colorectal cancer. Cancer Treat Rev 2003; 29 (4): 309–20PubMedCrossRef

29.

Blake J. Chemoinformatics: predicting the physiochemical properties of drug-like molecules. Curr Opin Biotechnol 2000; 11: 104–7PubMedCrossRef

30.

Gareth T. Medicinal chemistry. New York: John Wiley and Sons, 2000

31.

Gringauz A. Medicinal chemistry. New York: John Wiley and Sons, 1997

32.

Silverman R. The organic chemistry of drug design and drug action. San Diego (CA): Academic Press, 1992

33.

Hansch C, Leo A. Exploring QSAR. Washington (DC): American Chemical Society, 1995

34.

Lipinski C, Lombardo F, Dominy B, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23: 3–25CrossRef

35.

Clark D. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena: 2. Prediction of blood-brain barrier penetration. J Pharm Sci 1999; 88 (8): 815–20PubMedCrossRef

36.

Kelder J, Grootenhuis P, Bayada D, et al. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm Res 1999; 16 (10): 1514–9PubMedCrossRef

37.

Bartzatt R, Kasher L. Synthesis of aromatic nitrogen mustard agents and analysis of their alkylation activity at physiological pH and temperature. Physiol Chem Phys Med NMR 2002; 34: 103–17PubMed

38.

Pratt W, Ruddon R, Ensminger W, et al. The anticancer drugs. New York: Oxford University Press, 1994

39.

Kosaka R. Pharmaceuticals and drinks containing papain and citric acid for treatment of gynecological diseases. Japan Kokai Tokkyo Koho 1986: 1–3

40.

Dornberger K. Investigation on the potential antineoplastic constituents of Physalis alkekengi L. Var franchatii Mast. Pharmazie 1986; 41 (4): 265–8PubMed

41.

Mandronis K. Glyoxalic and citric acid preparation used for long life and cosmetic use, or for curing cancer, AIDS, and any pathological conditions. Athens: Patent Contents, 2003

42.

Zakem M, Davis B, Adelstein J, et al. Treatment of advanced stage mycosis fungoides with bleomycin, doxorubicin, and methotrexate with topical nitrogen mustard (BAM-M). Cancer 1986; 58 (12): 2611–6PubMedCrossRef

43.

Rassidakis G, Medeiros J, McDonnell T, et al. BAX expression in Hodgkin and Reed-Sternberg cells of Hodgkin’s disease: correlation with clinical outcome. Clin Cancer Res 2002; 8 (2): 488–93PubMed

44.

Straus D, Myers J, Koziner B, et al. Combination chemotherapy for the treatment of Hodgkin’s disease in relapse: results with lomustine (CCNU), melphalan (Alkeran), and vindesine (DVA) alone (CAD) and in alternation with MOPP and dox-orubicin (adriamycin), bleomycin, and vinblastine (ABV). Cancer Chemother Pharmacol 1983; 11 (2): 80–5PubMedCrossRef

Titel: Alkylation Activity and Molecular Properties of Two Antineoplastic Agents that Utilise Indometacin and a Conjugate of Aspirin with 2-Aminonicotinic Acid to Transport Nitrogen Mustard Groups
verfasst von: Dr Ronald Bartzatt
Publikationsdatum: 01.11.2007
Verlag: Springer International Publishing
Erschienen in: Drugs in R&D / Ausgabe 6/2007
Print ISSN: 1174-5886
Elektronische ISSN: 1179-6901
DOI: https://doi.org/10.2165/00126839-200708060-00004

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Alkylation Activity and Molecular Properties of Two Antineoplastic Agents that Utilise Indometacin and a Conjugate of Aspirin with 2-Aminonicotinic Acid to Transport Nitrogen Mustard Groups

Abstract

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 6/2007

Influence of Piperine on the Pharmacokinetics of Nevirapine under Fasting Conditions

Penetration of Prulifloxacin into Gynaecological Tissues after Single and Repeated Oral Administrations

The Rebif® New Formulation Story

Improving Early Drug Discovery through ADME Modelling

Megestrol Acetate NCD Oral Suspension — Par Pharmaceutical

MN 001