Antineoplastic Agents. 605. Isoquinstatins

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Cancer Research

Background:

• Dolastatin 10 is a potent anticancer agent and the parent molecule of the antibody drug conjugate (ADC) Adcetris.
• Previous studies explored quinoline-type structural modifications of dolastatin 10, leading to quinstatins.
• Antibody drug conjugates (ADCs) represent a successful therapeutic strategy in cancer treatment.

Purpose of the Study:

• To extend the study of quinstatins by replacing the quinoline ring with an isoquinoline moiety.
• To synthesize novel isoquinstatins and their N-terminal desmethyl derivatives.
• To prepare linker-desmethylisoquinstatin conjugates for potential monoclonal antibody attachment.

Main Methods:

• Synthesis of isoquinstatins (4-6) and N-terminal desmethylisoquinstatins (7-9).
• Conjugation of desmethylisoquinstatins to linker units to form conjugates (11-13).
• In vitro evaluation of isoquinstatins against six human cancer cell lines, determining GI50 values.

Main Results:

• Isoquinstatins exhibited GI50 values comparable to or slightly higher than their quinstatin counterparts.
• Desmethylisoquinstatin 5 (7) demonstrated significantly greater potency than its desmethylquinstatin 5 analogue.
• Isoquinstatin 8 (6) showed slightly less potency compared to its quinstatin 8 counterpart.
• The evaluated isoquinstatins acted as potent inhibitors of cancer cell growth.

Conclusions:

• The replacement of the quinoline ring with an isoquinoline in dolastatin 10 analogues yields potent anticancer agents.
• Specific structural modifications, such as N-terminal demethylation, can enhance cytotoxic potency.
• Isoquinstatins represent a promising class of compounds for further development in cancer therapy, including potential use in ADCs.