Carboplatin (Paraplatin)

4.12.1. Folic Acid Antagonists

The essential nature of folic acid at the cellular level was already noted in the discussion of the antibacterial sulfonamides (Chapter 2). It was indicated that tetrahydrofolic acid (FH4) was somehow necessary for the biosynthesis of purines and thymine, which, in turn, are the precursors of the nucleic acids. Consideration of some of these biochemical steps in somewhat greater detail is now necessary.



N5 - methylFH4 NH2

hs-ch2 ch2 -chcooh - "»» v-ch3 s-ch2 ch2 -chcooh

Transferase nh2 fh4 (4.9)

As shown in Figure 4-12, tetrahydrofolic acid, FH4 (see Fig. 2-3) picks up a one-carbon unit from L-serine (Eq. 4.8), and is converted to coenzyme N5,N'°-methylene-FH4, where the CH2 group bridges N5 and N10 of FH4. This coenzyme in turn is further oxidized to N5,N10-methylene-FH4. Addition of a water molecule across the N5 nitrogen-carbon bond affords N'°-formyl FH4 or Ns-formyl FH4. The latter is known as folinic acid, leucovorin, or citrovorum factor. Leucovorin is rapidly reducible to N5-methyl-FH4, the physiologically circulating folate. An alternate route to Nl0-formyl-FH4 is directly from FH4 by ATP-aided addition of formate. Interconversion thus also affords folinic acid. The various tetrahydrofolate coenzymes are the source for several one-carbon transfers, including the synthesis of L-methionine from L-homocysteine (Eq. 4.9), as will be seen in the biosynthesis of purine (see Fig. 4-14) forC-2 (N10-formyl FH4) and C-8 (N5,N'°-methenyl FH4). The conversion of deoxyuridylic acid (dUMP) to deoxythymidylic acid (dTMP) by the transfer of one-carbon fragment to the 5 position of the uracil from coenzyme N5,N'°-methylene-

Folate reductase Folate reductase _ Folic ku-» Dlhydrofollc acid (DHFA) -»■ Tetrahydrofolic acid (THFA)

Folate reductase Folate reductase _ Folic ku-» Dlhydrofollc acid (DHFA) -»■ Tetrahydrofolic acid (THFA)

N'-Formyl-THFA N ormyl-THFA

Figure 4-12. Folic acid and its derived coenzymes.


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