Amino Acids

, Volume 4, Issue 3, pp 287–302 | Cite as

The effects of boron containing peptides on L1210 lymphoid leukemia metabolism

  • I. H. Hall
  • E. S. Hall
  • M. C. MillerIII
  • A. Sood
  • B. F. Spielvogel


The purpose of this study was to establish the efficacy and mode of action of peptide boron derivatives as antineoplastic agents and to evaluate their safety in vivo. Boron-containing phenylalanine and tyrosine methyl esters were found to be potent cytotoxic agents in a number of murine and human cancer cell lines. DNA, RNA and protein syntheses were inhibited by selected agents, e.g. [(trimethylamine boryl)carbonyl]-phenylalanine-acetyl ester (9) andN-acetyl-p-boron-phenyl-alanyl-phenlalanine-methyl ester (10), in L1210 lymphoid leukemia cells. IMP dehydrogenase, OMP decarboxylase, m-RNA, t-RNA, r-RNA polymerase and ribonucleoside reductase activities were inhibited. d(CTP) levels were reduced. DNA strand scission occurred after 24 hr incubation. Acute toxicity studies in mice demonstrated that the key derivative was safe at therapeutic levels with no effects on histology of major organs, hematopoietic parameters and clinical values.


Amino acids Antineoplastic agents Boron peptide methyl esters Cytotoxicity L1210 leukemia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aaronson SA, Todaro GJ, Freeman AE (1970) Human sarcoma cells in culture. Exp Cell Res 61: 1Google Scholar
  2. Anderson KM, Mendelson IS, and Guzik G (1975) Solubilized DNA-dependent nuclear RNA polymerases from the mammary glands of late-pregnant rats. Biochem Biophys Acta 383: 56Google Scholar
  3. Appel SH (1968) Purification and kinetic properties of brain orotidine 5′-phosphate decarboxylase. J Biol Chem 243: 3924Google Scholar
  4. Archibald RM (1944) Determination of citrulline and allontoin and demonstration of citrulline in blood plasma. J. Biol Chem 156: 121Google Scholar
  5. Bagnara AS, Finch LR (1972) Quantitative extraction and estimation of intracellular nucleoside-triphosphate inEscherichia coli. Anal Biochem 45: 24Google Scholar
  6. Becker J, Lohr G (1979) Inosine-5′-phosphate dehydrogenase activity in normal and leukemic blood cells. Klin Wochenschr 57: 1109Google Scholar
  7. Brown BA (1984) Hematology: principals and procedures, 4th ed. Lea & Febiger, Philadelphia, p 29Google Scholar
  8. Cadman E, Heimer R, Benz C (1981) The influence of methotrexate pretreatment on S-flaxorouracil metabolism in L1210 cells. J Biol Chem 256: 1695Google Scholar
  9. Christopherson RI, Yu ML, and Jones ME (1981) An overall radioassay for the first three reactions of de novo pyrimidine synthesis. Anal Biochem 111: 240Google Scholar
  10. Eagle H (1955) Propagation in a fluid medium of a human epidermoid carcinoma strain KB. Proc Soc Exp Biol 89: 362–364Google Scholar
  11. Eichler DC, Fisher PA, Korn D (1977) Effect of calcium on the recovery distribution of DNA polymerase a from cultured human cells. J Biol Chem 252: 4011Google Scholar
  12. Geran RJ, Greenberg NM, MacDonald MM, Schumacher AM, Abbott BJ (1972) Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemo Rep 3: 9–24Google Scholar
  13. Hall IH, Carlson GL, Abernathy G, Piantadosi C (1974) Cycloalkanones IV. Antifertility agents. J Med Chem 17: 1253Google Scholar
  14. Hall IH, Spielvogel BF, Sood A (1990) The antineoplastic activity of trimethylamine carboxyboranes and related esters and amides in murine and human tumor cell lines. Anticancer Drugs 1: 133Google Scholar
  15. Hall IH, Morse KW, Spielvogel BF, Sood A (1991) DNA interaction with metal complexes and salts of substituted boranes and hydroborates in murine and human tumor cell lines. Anticancer Drugs 2: 389Google Scholar
  16. Harder HC, Rosenberg B (1970) Inhibitory effects of antitumor platinum compounds on DNA, RNA, and protein synthesis in mammalian cells. Int J Cancer 6: 207Google Scholar
  17. Ho YK, Hakala T, Zakrzewski SF (1971) 5-(1-Adamantyl) pyrimidines as inhibitors of folate metabolism. Cancer Res 32: 1023Google Scholar
  18. Howle JA, Gale GR (1970) Cis-dichlorodiammine plantinum (II): Persistent and selective inhibition of deoxyribonuclease acid synthesis in vivo. Biochem Pharmacol 19: 2757Google Scholar
  19. Hunting D, Henderson J (1982) Determination of deoxyribonucleoside triphosphates using DNA polymerase a: a critical evaluation. Can J Biochem 59: 723Google Scholar
  20. Kalman SM, Duffield PH, Brzozwki TJ (1966) Purification and properties of a bacterial carbamyl phosphate synthetase. J Biol Chem 241: 1871Google Scholar
  21. Kampf A, Barfknecht R, Schaffer P, Osaki S, Mertes M (1976) Synthetic inhibitors ofEscherichia coli calf thymus and Ehrlich ascites tumor thymidylate synthetase. J Med Chem 19: 903Google Scholar
  22. Koritz S, Gohen P (1968) Colorimetric determination of carbamyl amino acid and related compounds. J Biol Chem 243: 3924Google Scholar
  23. Leibovitz AL, Stinson JC, McComb III WB, McCoy CE, Mazur KC, Mabry ND (1976) Classification of human colorectal adenocarcinoma cell lines. Cancer Res 36: 4562Google Scholar
  24. Liao LL, Kupchan SM, Horwitz SB (1976) Mode of action of the antitumor compound bruceatin, an inhibitor of protein synthesis. Mol Pharmacol 12: 167–176Google Scholar
  25. Liu L, Davis J (1981) Novel topologically knotted DNA from bacteriophage P4 capsids: Studies with DNA topoisomerases. Nucleic Acids Res 9: 3979Google Scholar
  26. Lowry OH, Rosebrough J, Farr AL, Randall R (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193: 265Google Scholar
  27. Maley F, Ochoa S (1958) Enzymatic phosphorylation of deoxycytidylic acid. J Biol Chem 233: 1538Google Scholar
  28. Mamaril FP, Dobrjasky A, Green S (1970) A rapid method for isolation of nuclei of Ehrlich ascites tumor cells. Cancer Res 30: 352Google Scholar
  29. Miller KG, Lie LF, England PT (1981) A homogenous Type II DNA topoisomerase from HeLa cell nuclei. J Biol Chem 256: 9334Google Scholar
  30. Minowada J, Ohnuma T, and Moore GE (1972) Rosette-forming human lymphoid cell lines. 1. Establishment and evidence for origin of thymus-derived lymphocytes. J Natl Cancer Inst 49: 891Google Scholar
  31. Moore EC, Hurlbert RB (1966) Regulation of mammalian deoxyribonucleotide biosynthesis by nucleotide or activators and inhibitors. J Biol Chem 241: 4802Google Scholar
  32. Nelson-Rees WA, Flandermeyer RR, Hawthorne PK (1975) Distinctive banded marker chromosomes of human tumor cell lines. Int J Cancer 16: 74Google Scholar
  33. Ness AT, Pastewka JV, Peacock AC (1984) Evaluation of a recently reported stable Liebermann-Burchard reagent and its use for direct determination of serum total cholesterol. Clin Chem Acta 73: 812Google Scholar
  34. Oswald CB, Chaney SG, Hall IH (1990) Inhibition of nucleic acid synthesis in P388 lympocytic leukema cells in culture by cis-platinum derivatives. Biomed Biochim Acta 49: 579Google Scholar
  35. Pera JF Jr, Rawlings CJ, Shackleton J, Roberts JJ (1981) Quantitative aspects of the formation and loss of DNA interestrand crosslinks in Chinese hamster cell following treatment with cis-diaminodichloro-platinum (II) (cisplatin). II. Comparison and results from alkaline elution, DNA renaturation and DNA sedimentation studies. Biochem Biophys Acta 655: 152Google Scholar
  36. Puck TT, Marcus PI, Cieciura SJ (1956) Clonal growth of mammalian cells in vitro-growth characteristics of colonies from single HeLa cells with and without a ‘feeder’ layer. J Exp Med 103: 273Google Scholar
  37. Sawada H, Tatsumi K, Sadada M, Shirakawa S, Nakamura T, Wakisaka G (1974) Effects of neocarzinostatin on DNA synthesis in L1210 cells. Cancer Res 34: 3341Google Scholar
  38. Smith HS, Owens RB, Hiller, AJ, et al. (1976) The biology of human cells in tissue culture 1. Characterization of cells derived from osteogenic sarcoma. Int J Cancer 17: 219Google Scholar
  39. Snyder HR, Reedy AJ, Lennarz WJ (1958) Synthesis of aromatic boronic acids. Aldehydoboronic acids and boronic acid analogues of tyrosine. J Am Chem Soc 80: 835Google Scholar
  40. Sood A, Sood CK, Spielvogel BF, Hall IH (1990) Boron analogues of amino acids VI. Synthesis and characterization of di- and tripeptide analogues of antineoplastic, antiinflammatory and hypolipidemic agents. Eur J Med Chem 25: 301Google Scholar
  41. Sood CK, Sood A, Spielvogel BF, Yousef JA, Burnham B, Hall IH (1991) Synthesis and antineoplastic activity of some cyano-, carboxy-, carbo-methoxy-, and carbamoylborane adducts of heterocyclic amines. J Pharm Sci 80: 1133Google Scholar
  42. Spassova MK, Russev GC, Goovinsky EV (1976) Some pyrazoles as inhibitors of purine biosynthesis de novo. Biochem Pharmacol 25: 923Google Scholar
  43. Spielvogel BF, Sood A, Shaw BK, Hall IH (1991) From boron analoques of amino acids to boronated DNA: Potential new pharmaceutical and neutron capture agents. IME Boron VII, Poland, August 1990. Pure Appl Chem 63: 415Google Scholar
  44. Suzuki H, Nishimura T, Muto SK, Tanaka N (1978) Mechanism of action of macromomycin: DNA strand scission, inhibition of DNA synthesis and mytosis. J Antibact 32: 875Google Scholar
  45. Tietz NW (1976) Fundamentals of clinical chemistry. Saunders, Philadelphia, p 249Google Scholar
  46. Woynarowski JW, Beerman TA, Konopa J (1981) Induction of deoxyribonucleic acid damage in HeLa S3 cells by cytotoxic and antitumor sesquiterpine lactones. Biochem Pharmacol 30: 3005Google Scholar
  47. Zhao Y, Hall IH, Oswald CB, Yokoi T, Lee KH (1987) Antimalarial agents III. Mechanism of action of artesunate againstPlasmodium berghi infection. Chem Pharm Bull 35: 2052Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • I. H. Hall
    • 1
  • E. S. Hall
    • 1
  • M. C. MillerIII
    • 1
  • A. Sood
    • 2
  • B. F. Spielvogel
    • 2
  1. 1.Division of Medicinal Chemistry and Natural ProductsUniversity of North Carolina at Chapel HillUSA
  2. 2.Boron Biologicals, IncRaleighUSA

Personalised recommendations