N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

Eric Lattmann, Steven T Russell, Mankaran Singh, Ramesh Narayanan, Padinjarethalakal N. Balaram, Pornthip Lattmann

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)180-189
JournalDrug Design, Development and Therapy
Volume2
Issue number4
DOIs
Publication statusPublished - 6 Jul 2018

Fingerprint

Gastrins
Antineoplastic Agents
Lung Neoplasms
Nude Mice
Cell Line
Therapeutics
Drug Design
Cholecystokinin
Anti-Anxiety Agents
Duodenum
Heterografts
Colonic Neoplasms
Inhibitory Concentration 50
Oral Administration
Intercellular Signaling Peptides and Proteins
Breast Neoplasms
Growth
Pharmaceutical Preparations
In Vitro Techniques
Neoplasms

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.

Cite this

Lattmann, Eric ; Russell, Steven T ; Singh, Mankaran ; Narayanan, Ramesh ; Balaram, Padinjarethalakal N. ; Lattmann, Pornthip. / N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer. In: Drug Design, Development and Therapy. 2018 ; Vol. 2, No. 4. pp. 180-189.
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abstract = "Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumoursand CCK1R and CCK2R receptors are ideal molecular targets for novel smart chemo‒therapeutics with a beneficial overall profile due to their anxiolytic and antidepressantproperties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK2R)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 renewablebiomass was performed. After initial radiolabelled receptor binding studies with hotCCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmedCCK antagonism. Cell based studies using the MTT assay provided a candidate for invivo xenograft models with nude mice. Rational drug design was supported by molecularmodelling experiments.Results: Potent and selective CCK antagonists were prepared as stable crystalline materialsin high yields. Gastrin antagonists were in vitro active on isolated tissue preparationsand inhibited breast, colon and lung cancer cell lines in vitro with IC50 to 45nM for theprivileged 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 oftumour growths by oral administration in athymic mice transplanted with the human lungcancer cell line H727.Conclusion: PNB‒101 is a potential chemotherapeutic agent for CCK‒gastrin relatedcancers and entered preclinical development.",
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N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer. / Lattmann, Eric; Russell, Steven T; Singh, Mankaran; Narayanan, Ramesh; Balaram, Padinjarethalakal N.; Lattmann, Pornthip.

In: Drug Design, Development and Therapy, Vol. 2, No. 4, 06.07.2018, p. 180-189.

Research output: Contribution to journalArticle

TY - JOUR

T1 - N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

AU - Lattmann, Eric

AU - Russell, Steven T

AU - Singh, Mankaran

AU - Narayanan, Ramesh

AU - Balaram, Padinjarethalakal N.

AU - Lattmann, Pornthip

N1 - © 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.

PY - 2018/7/6

Y1 - 2018/7/6

N2 - Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumoursand CCK1R and CCK2R receptors are ideal molecular targets for novel smart chemo‒therapeutics with a beneficial overall profile due to their anxiolytic and antidepressantproperties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK2R)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 renewablebiomass was performed. After initial radiolabelled receptor binding studies with hotCCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmedCCK antagonism. Cell based studies using the MTT assay provided a candidate for invivo xenograft models with nude mice. Rational drug design was supported by molecularmodelling experiments.Results: Potent and selective CCK antagonists were prepared as stable crystalline materialsin high yields. Gastrin antagonists were in vitro active on isolated tissue preparationsand inhibited breast, colon and lung cancer cell lines in vitro with IC50 to 45nM for theprivileged 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 oftumour growths by oral administration in athymic mice transplanted with the human lungcancer cell line H727.Conclusion: PNB‒101 is a potential chemotherapeutic agent for CCK‒gastrin relatedcancers and entered preclinical development.

AB - Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumoursand CCK1R and CCK2R receptors are ideal molecular targets for novel smart chemo‒therapeutics with a beneficial overall profile due to their anxiolytic and antidepressantproperties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK2R)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 renewablebiomass was performed. After initial radiolabelled receptor binding studies with hotCCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmedCCK antagonism. Cell based studies using the MTT assay provided a candidate for invivo xenograft models with nude mice. Rational drug design was supported by molecularmodelling experiments.Results: Potent and selective CCK antagonists were prepared as stable crystalline materialsin high yields. Gastrin antagonists were in vitro active on isolated tissue preparationsand inhibited breast, colon and lung cancer cell lines in vitro with IC50 to 45nM for theprivileged 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 oftumour growths by oral administration in athymic mice transplanted with the human lungcancer cell line H727.Conclusion: PNB‒101 is a potential chemotherapeutic agent for CCK‒gastrin relatedcancers and entered preclinical development.

U2 - 10.15406/mojddt.2018.02.00045

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M3 - Article

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