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Paper | Regular issue | Vol 51, No. 8, 1999, pp.1789-1805
Published online, 1st January, 1970
DOI: 10.3987/COM-99-8505
Synthesis of the g-Sulfinic Acid and g-Nitro Analogues of 5-Deazatetrahydrofolic Acid

Ronald A. Forsch, Joel E. Wright, and Andre Rosowsky*

*Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, U. S. A.


Analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid with a γ-sulfinic acid group or γ-nitro group in place of the γ-carboxyl group of the glutamate side chain were synthesized as diastereomeric mixtures, and were tested for their ability to in-hibit the growth of CCRF-CEM human leukemia cells in culture. The concentration of the γ-sulfinic acid analogue (7) giving 50% inhibition of growth during 120 h of continuous drug treatment was 21 μM versus 93 μM for the γ-nitro analogue (8). The Ki of 7 as a competitive inhibitor of the influx of [3H]methotrexate into CCRF-CEM cells via the reduced folate carrier (RFC) was 5.0 μM, a value close to the Km values typically cited in the literature for MTX and natural reduced folates. Thus, apart from any other mechanistic targets this compound might have, 7 has the potential to deplete endogenous pools of reduced folates in dividing cells by interfering with RFC function.