Medicinal Chemistry

7.8.4 Targeting Nucleic Acids: Drug Design Approaches

7.8.4.1 Designing Cell-Cycle-Specific Agents

In designing drugs to target the cell nucleus, it is imperative to remember that the cell
nucleus is a biochemically dynamic structure. For reproductively active cells, nucleic acid
biosynthesis occurs in stages within the cellular nucleus. This gives rise to the concept of
acell cyclein which the cell exits in four distinct phases: S (DNA synthesis), M (mitosis,
cell division), G 1 (a resting phase in which cellular components for DNA synthesis may be
produced), and G 2 (a resting phase in which cellular components for mitosis may be syn-
thesized). The G 1 phase contains a G 0 phase, in which the cell is not active in cell division.
The major classes of drugs used in cancer chemotherapy may be either cell-cycle-specific
(CCS) or cell-cycle-nonspecific (CCNS), depending upon their mode of interference with
the replication–transcription–translation cascade. CCS agents include antimetabolites (e.g.,
methotrexate, 5-FU, thioguanine), podophyllin alkaloids (e.g., etoposide, teniposide) and
plant alkaloids (e.g., vincristine, paclitaxel); CCNS agents include alkylating agents,
cisplatin, and antibiotic anticancer drugs (e.g., daunorubicin, doxorubicin).

7.8.4.2 Designing Rational Polypharmacy Agents

In drug design, it is sometimes possible to design new drugs to act synergistically with
other existing drugs. This would lead to rational polytherapy—the purposeful therapeu-
tic combination of two or more drugs with complementary mechanisms of action.
Typically, monotherapy (the use of one “ideal” drug for the disease in question) is prefer-
able. However, in complicated disease states, such as those presented by cancer, poly-
therapy (also called polypharmacy) is frequently desirable. The fact that the anticancer
agents all work by interfering with DNA/RNA, but do so by differing and noncompeti-
tive molecular mechanisms, enables such agents to be combined in a rational (and hope-
fully synergistic) manner. A large number of “combination cancer chemotherapeutic
regimens” are in common clinical use. A partial listing of such regimens includes:

1. Breast cancer
   a. Doxorubicin +cyclophosphamide +paclitaxel
   b. Doxorubicin +cyclophosphamide +methotrexate +fluorouracil


2. Bladder cancer
   Methotrexate +vinblastine+doxorubicin+cisplatin


3. Testicular cancer
   Bleomycin+etoposide+cisplatin


4. Ovarian cancer
   Paclitaxel +carboplatin


5. Lung cancer
   Cyclophosphamide+doxorubicin+vincristine+etoposide+cisplatin

7.8.5 Emerging Trends in Cancer Drug Design

The diverse compounds discussed above as putative therapies for cancer tend to exhibit
significant toxicities that arise from their inability to differentiate between the DNA of
the tumor and the DNA of the host patient. Accordingly, several new directions in

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