Abstract
Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumours
and CCK1
R and CCK2R receptors are ideal molecular targets for novel smart chemo‒
therapeutics with a beneficial overall profile due to their anxiolytic and antidepressant
properties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK2
R)
antagonists are ideal experimental drug candidates.
Objective: Synthesis and evaluation of novel CCK antagonists, most preferred CCK2
/
gastrin selective for the treatment of lung cancers.
Methods: A fast and efficient synthesis of hydroxy‒pyrrolones in 2 steps from renewable
biomass was performed. After initial radiolabelled receptor binding studies with hot
CCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmed
CCK antagonism. Cell based studies using the MTT assay provided a candidate for in
vivo xenograft models with nude mice. Rational drug design was supported by molecular
modelling experiments.
Results: Potent and selective CCK antagonists were prepared as stable crystalline materials
in high yields. Gastrin antagonists were in vitro active on isolated tissue preparations
and inhibited breast, colon and lung cancer cell lines in vitro with IC50 to 45nM for the
privileged hydroxyl‒pyrrolone lead structure in the MTT assay for human cancer cell lines.
PNB‒101, a fluorinated 5‒hydroxy‒5‒aryl‒pyrrol‒2‒one, gave up to 80% inhibition of
tumour growths by oral administration in athymic mice transplanted with the human lung
cancer cell line H727.
Conclusion: PNB‒101 is a potential chemotherapeutic agent for CCK‒gastrin related
cancers and entered preclinical development.
and CCK1
R and CCK2R receptors are ideal molecular targets for novel smart chemo‒
therapeutics with a beneficial overall profile due to their anxiolytic and antidepressant
properties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK2
R)
antagonists are ideal experimental drug candidates.
Objective: Synthesis and evaluation of novel CCK antagonists, most preferred CCK2
/
gastrin selective for the treatment of lung cancers.
Methods: A fast and efficient synthesis of hydroxy‒pyrrolones in 2 steps from renewable
biomass was performed. After initial radiolabelled receptor binding studies with hot
CCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmed
CCK antagonism. Cell based studies using the MTT assay provided a candidate for in
vivo xenograft models with nude mice. Rational drug design was supported by molecular
modelling experiments.
Results: Potent and selective CCK antagonists were prepared as stable crystalline materials
in high yields. Gastrin antagonists were in vitro active on isolated tissue preparations
and inhibited breast, colon and lung cancer cell lines in vitro with IC50 to 45nM for the
privileged hydroxyl‒pyrrolone lead structure in the MTT assay for human cancer cell lines.
PNB‒101, a fluorinated 5‒hydroxy‒5‒aryl‒pyrrol‒2‒one, gave up to 80% inhibition of
tumour growths by oral administration in athymic mice transplanted with the human lung
cancer cell line H727.
Conclusion: PNB‒101 is a potential chemotherapeutic agent for CCK‒gastrin related
cancers and entered preclinical development.
| Original language | English |
|---|---|
| Pages (from-to) | 180-189 |
| Journal | Drug Design, Development and Therapy |
| Volume | 2 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 6 Jul 2018 |
Bibliographical note
© 2018 Lattmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License,which permits unrestricted use, distribution, and build upon your work non-commercially.