Actinomycin Antitumor Antibiotics. Actinomycin D (7.56), produced by the fungus
Actinomyces antibioticus, is an effective tumor-inhibiting antibiotic. It is a phenoxa-
zone derivative with two cyclic pentapeptide side chains pointing up and down from the
plane of the heterocyclic nucleus. The peptides form hydrogen bonds with each other.
Actinomycin D forms a strong complex with double-stranded DNA (KD= 5 × 10 −^6 M) at
G–C pairs, binding to the 2-amino group of the guanine. The flat heterocyclic ring is
intercalated. The compound selectively inhibits the ribosomal RNA chain-elongation step
during transcription. Although a very effective drug in certain malignancies (testicular
tumors, disseminated cancers), it is a very toxic compound. F8-AMD (7.58) is a struc-
turally related antitumor antibiotic.
Anthracycline Antitumor Antibiotics. The group of anthracycline antibiotics, used
in the treatment of several forms of cancer, includes doxorubicin (7.59) and dauno-
mycin (7.54), which differ by only one hydroxyl group. Both are aminoglycosides of
anthraquinones produced by some Streptomycesspecies, and are related to the antibac-
terial tetracyclines. The four-membered ring system intercalates into DNA, entering
from the major groove. The sugar moiety of the drug is ion-bonded through its amino
group to the phosphate backbone of DNA. Daunomycin is used primarily in acute
leukemia, but adriamycin is effective in solid tumors also. The 4-desmethoxy deriva-
tives of both compounds are much more potent. The principal drawback of these active
cancer chemotherapeutic agents is their severe cardiotoxicity, acting through the inhi-
bition of cardiac Na+,K+-ATPase. Idarubicin (7.60) and epirubicin (7.61) are more
recent analogs in this class of compounds.
From a molecular structural perspective, it is the presence of planar aromatic “build-
ing blocks” within these molecules that enable them to intercalate into the DNA.
However, this planar aromatic structure is also responsible for many molecules being
ENDOGENOUS CELLULAR STRUCTURES 445Figure 7.5 Intercalation of carcinogens into the stacked bases of nucleic acids. Both carcinogens
and certain anti-neoplastic agents share a common mechanism of action. They have the capacity
to insert themselves into the nucleic acid structure, causing geometrical distortions that preclude
the ability of the nucleic acid to complete its function in the processes of transcription and trans-
lation. Flat aromatic molecules have the ability to intercalate between the stacked bases.