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Investigational New Drugs

, Volume 21, Issue 1, pp 47–54 | Cite as

An Overview on the Antileukemic Potential of D-homo-aza- and Respective 17β-Acetamido-Steroidal Alkylating Esters

  • Charalambos Camoutsis
  • Dimitrios T.P. Trafalis
Article

Abstract

In order to reduce toxicity and to increase antineoplastic activity, steroid molecules were utilized as biological vectors for chemotherapeutic agents. Several modified steroid compounds as 17β-acetamido and D-homo-aza steroids that contain the NHCO group outside or inside D steroid ring, respectively, were used in the synthesis of steroidal esters carrying alkylating moieties. As it has been reported previously, several of these compounds produced important both antileukemic and antitumor results. In this work, we comparatively study, evaluate, and conclude on the acute toxicity on mice, the in vivo antileukemic activity against P388 and L1210 murine leukemias, as well the in vitro antileukemic effect on three well established human leukemia cell lines (K562, MOLT-4, ML-1) of eight D-homo-aza-steroidal (HASE) and the corresponding steroidal 17β-amido-esters (SAE) of three alkylating molecules. The compound screening indicated that HASE induced lower acute toxicity and significant higher antileukemic effect than SAE, both in vivo and in vitro. Furthermore, the structure of the homo-aza-steroidal vector seems to be a determinant of the toxicity and antineoplastic activity of the esters. Conclusively, HASE presented low acute toxicity but significant high antileukemic activity. These results point out that HASE may be of important therapeutic efficacy in the treatment of leukemia in humans.

acetamido steroidal esters homo-aza steroids alkylators P388 lymphocytic leukemia L1210 lymphoid leukemia human leukemia cell lines acute toxicity 

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References

  1. 1.
    Wall ME, Abernethy SG, Carroll JFI, Taylor DJ: The effects of some steroidal alkylating agents on experimental animal mammary tumor and leukemia systems. J Med Chem 12: 810–818, 1969Google Scholar
  2. 2.
    Wampler GL, Catsoulacos P: Antileukemic effect of homo-aza-steroidal-ester of [p-[bis(2–chloroethyl)amino]acetic acid. Cancer Treat Rep 61: 37–41, 1977Google Scholar
  3. 3.
    Catsoulacos P, Camoutsis C, Wampler GL: Effect of a Δ5–homo-aza-steroidal ester in P388 and L1210 murine leukemias. Oncology 39: 59–60, 1982Google Scholar
  4. 4.
    Catsoulacos P, Politis D, Wampler GL: A new steroidal alkylating agent with improved activity in advanced murine leukemias. Cancer Chemother Pharmacol 3: 67–70, 1979Google Scholar
  5. 5.
    Catsoulacos P, Wampler GL: Activity of 3β-hydroxy-13α-amino-13,17–seco-5α-androstan-17–oic-13,17–lactam(p-bis(2–chloroethyl)amino)-phenyl)acetate (NSC-290205) in murine solid tumors. Oncology 39: 109–112, 1982Google Scholar
  6. 6.
    Catsoulacos P: Further studies on the anti-neoplastic activity of 3β-hydroxy-13α-amino-13,17–seco-5α-androstan-17–oic-13,17–lactam(p-bis(2–chloroethyl)amino)-phenyl) acetate (NSC-290205). Cancer Lett 22: 199–202, 1984Google Scholar
  7. 7.
    Catsoulacos P: Activity of 3β-hydroxy-13α-amino-13,17–seco-5α-androstan-17–oic-13,17–lactam p-bis (2–chloroethyl) aminophenyoxy acetate (NSC-294859) on experimental tumor and leukemia systems. Oncology 40: 290–292, 1983Google Scholar
  8. 8.
    Catsoulacos P, Catsoulacos D: Antitumor activity of homo-aza-steroidal esters of p-N,N-bis(2–chloroethyl) amino phenoxy acetic acid. Anticancer Res 13: 1203–1208, 1993Google Scholar
  9. 9.
    Catsoulacos P, Boutis L: Antitumor activity of a homo-aza-steroidal ester of p-bis(2–chloroethyl)aminophenyl acetic acid. Cancer Chem Rep 57: 365–367, 1973Google Scholar
  10. 10.
    Finlay GJ, Wilson WR, Baguley BC: Comparison of in vitro activity of cytotoxic drugs towards human carcinoma and leukaemia cell linesa. Eur J Cancer Clin Oncol 22: 655–662, 1986Google Scholar
  11. 11.
    Catsoulacos P, Politis D, Wampler GL: Antitumor activity of homo-aza-steroidal esters of [p-bis(2–chloroethyl)amino] phenyl]acetic acid [p-bis(2–chloroethyl) amino]phenyl] butyric acid. Cancer Chemother Pharmacol 10: 129–132, 1983Google Scholar
  12. 12.
    Pairas G, Catsoulacos P: On the synthesis of homo-aza-steroidal esters. Eur J Med Chem 21: 525–526, 1986Google Scholar
  13. 13.
    Pairas G, Catsoulacos P, Papageorgiou A, Boutis L: Further studies on the antineoplastic activity of homo-aza-steroidal esters. Oncology 43: 344–348, 1986Google Scholar
  14. 14.
    Papageorgiou A, Boutis L, Nicolaropoulos S, Catsoulacos P: Potential antitumor agents: Steroidal amidoesters with an alkylating moiety. Oncology 44: 128–132, 1987Google Scholar
  15. 15.
    Anastasiou A, Catsoulacos P, Papageorgiou A, Margariti E: On the formation of homo-aza steroidal esters of N,N-bis(2–chloroethyl)amino benzoic acid isomers and their antitumor activity. J Heterocyclic Chem 31: 367–373, 1994Google Scholar
  16. 16.
    Papageorgiou A, Catsoulacos P, Catsoulacos D, Mourelatos D, Mioglou-Kalouptsi E, Iakovidou-Kristi Z, Boutis L, Kotsis A: A comparative study of the cytogenetic and antineoplastic effects induced by steroidal amidoesters of p-N,N-bis(2–chloroethyl)aminophenylbutyric acid. Cancer J 9: 203–206, 1996Google Scholar
  17. 17.
    Ma D, Wamg G, Wang S, Kozikowski AP, Lewin NE, Blumberg PM: Synthesis and protein kinase C binding activity of benzolactam-V-7. Bioorg Med Chem Lett 9: 1371–1374, 1999Google Scholar
  18. 18.
    Endo Y, Yokohama A: Role of the hydrophobic moiety of tumor promoters. Synthesis and activity of 2–alkylated benzolactams. Bioorg Med Chem Lett 10: 63–66, 2000Google Scholar
  19. 19.
    Endo Y, Shimazu M, Fukusawa H, Driedger PE, Kimura K, Tomioka N, Itai A, Shudo K: Synthesis computer modeling and biological evaluation of novel protein kinase C agonists based on a 7–membered lactam moiety. Bioorg Med Chem Lett 9: 173–178, 1999Google Scholar
  20. 20.
    Irie K, Koizumi F, Iwata Y, Ishii T, Yanai Y, Nakamura Y, Ohigashi H, Wender PA: Synthesis and biological activities of new conformationally fixed analogues of ()-indolactam-V the core structure of tumor promoting teleocidins. Bioorg Med Chem Lett 5: 453–458, 1995Google Scholar
  21. 21.
    Smith RF, Shay DE, Doorenbos NJ: Antimicrobial action of nitrogen-containing steroids. J Bacteriol 85: 1295–1299, 1963Google Scholar
  22. 22.
    Kabara JJ, Holzschu DL, Catsoulacos P: Structure-function activity of azasterols and nitrogen-containing steroids. Lipids 11: 755–762, 1976Google Scholar
  23. 23.
    Catsoulacos P, Camoutsis C, Papageorgiou A, Adamiak-Margariti E: Cytostatic effect of homo-aza-steroidal esters in vivo and in vitro structure-activity relationships. Anticancer Res 12: 1617–1620, 1992Google Scholar
  24. 24.
    Dalmases P, Gomez-Belinchon JI, Bonet J-J, Giner-Sorolla A, Schmid FA: Antineoplastic agents. II. A nitrogen mustard derivative of N-methylated steroidal lactam. Eur J Med Chem 18: 541–543, 1983Google Scholar
  25. 25.
    Dalmases P, Cervantes G, Quintana J, Bonet J-J: Antineoplastic agents. V. Nitrogen mustards of systematically modified steroidal ring A lactams. Eur J Med Chem 19: 465–467, 1984Google Scholar
  26. 26.
    Catsoulacos P, Camoutsis Ch, Papageorgiou A, Margariti E, Psaraki K, Demopoulos N: Structure-anticancer and structure-genetic activity relationships of homo-aza-steroidal esters of N,N-bis(2–chloroethyl)aminocinnamic acid isomers. J Pharm Sci 82: 204–208, 1993Google Scholar
  27. 27.
    Catsoulacos P, Catsoulacos D: Conjugated system of homo-aza-steroidal esters in cancer chemotherapy. Anticancer Res 14: 2525–2528, 1994Google Scholar
  28. 28.
    Catsoulacos P, Pairas G, Papageorgiou A: On the formation of estrone lactam esters of N,N-bis(2–chloroethyl)aminocinnamic acid isomers, N,N-bis(2–chloro ethyl)aminophenyl-butyric acid and their antitumor activity. J Heterocyclic Chem 32: 1063–1065, 1995Google Scholar
  29. 29.
    Camoutsis C, Sampani C, Trafalis DTP, Peristeris P: On the formation of steroidal amidoesters of p-[N,N-bis(2–chloroethyl)amino]benzoic acid and their cytotoxic activity. Eur J Med Chem 34: 645–649, 1999Google Scholar
  30. 30.
    Catsoulacos P, Papageorgiou A, Margariti E, Mourelatos D, Mioglou E: Comparison of current alkylating agents with a homo-aza-steroidal ester for antineoplastic activity. Oncology 51: 74–78, 1994Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Charalambos Camoutsis
    • 1
  • Dimitrios T.P. Trafalis
    • 1
  1. 1.Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health ScienceUniversity of PatrasGreece

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