Medicinal Chemistry

7.8.2.2 Synthetic Anti-Transcription Agents

Another group of agents that interfere with DNA transcription are the platinum
complexes. The cis-dichlorodiammine-platinum (II) complex (7.88, cisplatin), but not the
transisomer, is very active against testicular tumors, epidermoid carcinomas, and ovar-
ian tumours. Cisplatin is prepared by treating potassium chloroplatinite with ammonia.
It binds strongly to DNA by intrastrand binding (i.e., not crosslinking) to oligoguanine
sequences, unwinds the duplex, and reduces the length of the DNA molecule. The trans
isomer is selectively removed from the DNA. These platinum agents are therefore
similar, but not identical, to alkylating agents. By binding to DNA, this compound
ultimately inhibits the transcription process.

Many platinum analogs, and analogs based on other metal centres, have been prepared
and evaluated. Carboplatin (7.89,cis-diammine(1,1 cyclobutanedicarboxalato)platinum)
has markedly reduced gastrointestinal and renal toxicity in comparison with cisplatin.
It is prepared by the treatment of cis-Pt(NH 3 ) 2 I 2 with silver sulphate, followed by the
barium salt of 1,1-cyclobutanedicarboxylic acid.

7.8.2.3 Antisense Oligomer Anti-Translation Agents

Antisense oligomers provide a rational approach to the inhibition of translation.
Single-strand messenger RNA (mRNA) demonstrates high-affinity, sequence-specific
binding to a complementary oligonucleotide sequence (via hydrogen bonding of the
Watson–Crick pairs). This complementary agent is termed an antisense oligomer.
Antisense oligomers can block RNA translation into protein. Since they are analogs of
endogenous natural products, antisense oligomers are readily susceptible to enzymatic
degradation. This problem can be addressed by the bioisosteric replacement of “build-
ing block” segments within the antisense oligomer. For instance, the sugar–phosphate
backbone has been replaced with N-(2-aminoethyl)glycine units. Similarly, the sugar
moieties have been replaced using 2′-fluoro-2′-deoxysugars. From a clinical perspec-
tive, these agents are still in their developmental stages.

7.8.3 Cytostatic Agents Interfering with Mitosis

During the metaphase stage of mitosis, the daughter chromosomes normally begin to
migrate toward the poles of the cell; they are pulled toward the poles by microtubules, which

454 MEDICINAL CHEMISTRY

Carboplatin (7.89)