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Abstract

A Facile High-Yield Synthesis of [10 B]-8-Dihydroxyboryl Harmine, a Potential Agent for Boron Neutron Capture Therapy

PROPLAME-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires, Argentina
*
Author to whom correspondence should be addressed.
Molecules 2000, 5(3), 526-528; https://doi.org/10.3390/50300526
Published: 22 March 2000
The resurgence of interest in Boron Neutron Capture Therapy (BNCT) as a treatment for malignant lesions has resulted in the synthesis of numerous boron compounds as candidates for clinical use. BNCT is a selective radiotherapy using boron-10 which absorbs thermal neutrons and releases high Linear Energy Transfer (LET) alpha particles by 10 B (n, α) 7 Li reaction. The alpha radiation kills cells in the range of 5-9 μm from the site of the α generation. Therefore, it is theoretically possible to kill tumor cells without affecting adjacent healthy tissues, if 10 B-compounds could be selectively delivered. Boron analogues of amino acids constitute a topic of major importance, and also peptides, antibodies, nucleosides and nucleotides [1], etc. In spite of the promising results with p-boronophenylalanine (BPA) and B12H11SH2-(Na+) (BSH), which presently attract considerable clinical interest, they display far from optimal selectivity for cancer cells.
The anatomical distribution of [3H]Harmalas binding sites was determined by quantitative autoradiography in rat brain slices [2]. They have a well know brain distribution, so these compounds, labeled with 10B are potential agents for BNCT. A general synthetic method has been developed for the rapid and efficient production of boronated Harmine.

Results And Discussion

Iodination

The methods for iodination have been used previously for indolealkylamine [4] and phenethyla- mines [4] using thallium trifluoroacetate as specific oxidizing agent of molecular iodine for iodination of aromatic compounds [5].

Boronation

We used the condensation of the Grignard reagent from 8-I-Harmine with trimethylborate. This method was previously used [6] for preparation of phenol from phenylbromide and trimethylborate with formation of phenylboronic acid as intermediate and for preparation of boronic analogue of choline [7]. An alternative synthesis previously used for preparation of boronic analogues of nucleosides and nucleic bases [8,9,10,11] consist in treating the halogenated substrate with n-buthyllithium in THF followed by addition of trimethylborate at –86°C. Trimethylborate was prepared by standard procedures [12] from 95% 10B-enriched or natural isotope abundance boric acid and methanol and recovered from the formed azeotrope.

Summary and Conclusions

We have described a method for preparation of [10B]-enriched-8-dihydroxyborylharmine (III) and characterized it by their spectral properties (MS, IR and NMR). This compound is a potential BNCT agent.

Acknowledgments 

Thanks are due to CONICET and Universidad de Buenos Aires (UBA; Argentina) for financial support. One of us, (J.A.S), also thank CONICET for research fellowship.

References and Notes

  1. Morin, C. Tetrahedron 1994, 50, 12521. [CrossRef]
  2. Pawlik, M.; Kaulen, P.; Baumgarten, H.G.; Rommelspacher, H. Journal of Neuroanathomy 1990, 3, 19.
  3. Sintas, J.A.; Vitale, A.A. J. Lab Comp. Radioparm. 1997, 39, 676.
  4. Sintas, J.A.; Vitale, A.A. J. Lab Comp. Radioparm. 1998, 41, 53. [CrossRef]
  5. McKillop, A.; Hunt, J.D.; Zelesko, M.J. J. Am. Chem Soc. 1971, 93, 4841. [CrossRef]
  6. Hawthorne, M.F. J. Org. Chem. 1957, 22, 1001. [CrossRef]
  7. Koehler, K.A.; Hess, G.P. Biochemistry 1974, 13, 5345. [CrossRef] [PubMed]
  8. Liao, T.K.; Prodrebarac, E.G.; Cheng, C.C. J. Am. Chem. Soc. 1964, 86, 1869. [CrossRef]
  9. Schinazi, R.F.; Prusoff, W.H. Tetrahedron Lett. 1978, 4981.
  10. Schinazi, R.F.; Prusoff, W.H. J. Org. Chem. 1985, 50, 841. [CrossRef]
  11. Tjarks, W.; Gabel, D.J. J. Med. Chem. 1991, 34, 315. [CrossRef] [PubMed]
  12. Shlesinguer, H.I.; Browz, H.C.; Mayfield, D.L. J. Am. Chem. Soc. 1953, 71, 213.
  13. Hall, L.W.; Odon, J.D.; Ellis, P.D. J. Am. Chem. Soc. 1975, 97, 4527. [CrossRef]
Scheme 1. Synthesis of boronated harmine.
Scheme 1. Synthesis of boronated harmine.
Molecules 05 00526 sch001

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MDPI and ACS Style

Sintas, J.A.; Macareno, N.J.; Vitale, A.A. A Facile High-Yield Synthesis of [10 B]-8-Dihydroxyboryl Harmine, a Potential Agent for Boron Neutron Capture Therapy. Molecules 2000, 5, 526-528. https://doi.org/10.3390/50300526

AMA Style

Sintas JA, Macareno NJ, Vitale AA. A Facile High-Yield Synthesis of [10 B]-8-Dihydroxyboryl Harmine, a Potential Agent for Boron Neutron Capture Therapy. Molecules. 2000; 5(3):526-528. https://doi.org/10.3390/50300526

Chicago/Turabian Style

Sintas, Jose A., Norberto J. Macareno, and Arturo A. Vitale. 2000. "A Facile High-Yield Synthesis of [10 B]-8-Dihydroxyboryl Harmine, a Potential Agent for Boron Neutron Capture Therapy" Molecules 5, no. 3: 526-528. https://doi.org/10.3390/50300526

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