Synthesis and antitumor effects of novel 18β-glycyrrhetinic acid derivatives featuring an exocyclic α,β-unsaturated carbonyl moiety in ring A

Article abstract of DOI:10.1016/j.bioorg.2020.104187

A series of novel 18β-glycyrrhetinic acid (GA) derivatives featuring an exocyclic α,β-unsaturated carbonyl moiety in ring A were synthesized and evaluated for their antitumor activities. Compounds 5c and 5l showed stronger cytotoxicity than other compounds and reported GA analogue CDODA-Me (methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate). 5c and 5l induced apoptosis in cancer cells accompanying with c-Flip reduction and Noxa induction, associated with decreased HDAC3 expression and increased acetylation of H3. 5l displayed better stability properties than 5c and CDODA-Me in microsomes and plasma, 5l also showed favorable pharmacokinetic profiles and inhibited tumor growth in mice. Compound 5l represents a new type of GA derivatives with improved antitumor activity.

Full text of DOI:10.1016/j.bioorg.2020.104187

January 2017
Abstracts
S461
Conclusion: Overall, Our findings suggest that catechin 5%, 7%, 9%, and 11%; and differed significantly by
hydrate inhibits B(a)P-induced lung tumor formation by smoking status (p¼0.0539, p¼0.0316, p¼0.0187,
modulating hyperproliferation, inflammation, apoptosis p¼0.0017). At 5 years, overall survival was 69% for
and ALDH1 expression.
never smokers, 55% for active, and 49% for former
smokers (p¼0.0002) (Figure 1). Controlling for age, sex,
race, insurance, histologic grade, extent of resection, and
length of surgery, and compared with never smokers,
active smokers had 1.3 times (p¼0.05) the hazard of
death and former smokers had 1.4 times the hazard of
death (p¼0.04).
Keywords: Catechin hydrate, aldehyde dehydrogenase
1
, carcinoembryonic antigen, chemoprevention
P1.01-021
The Impact of Smoking Status on
Overall Survival in a Population-Based
Non-Small Cell Lung Cancer (NSCLC)
Surgical Resection Cohort
Topic: Protective Factors, Risk Reduction,
Smoking Cessation
1
2
2
Nicholas Faris, Yu-Sheng Lee, Meghan Meadows,
2
2
2
Matthew Smeltzer, Meredith Ray, Kenneth Ward,
1
3
Carrie Fehnel, Cheryl Houston-Harris,
3
1
Raymond Osarogiagbon Thoracic Oncology Research
Group, Multidisciplinary Thoracic Oncology Program,
Baptist Cancer Center, Memphis/TN/United States of
America, School of Public Health, University of Memphis,
Memphis/TN/United States of America, Thoracic
2
3
Oncology Research Group, Multidisciplinary Thoracic
Oncology Program, Baptist Cancer Center, Memphis/
United States of America
Conclusion: In this population-based cohort, smoking is
negatively associated with post-operative mortality and
long-term overall patient survival; although active
smokers had better survival outcomes than former
smokers.
Background: Surgical resection is the optimal treat-
ment modality for NSCLC, while smoking has been
shown to have a negative survival impact. We evalu-
ated smoking’s impact on overall survival within a
population-based cohort of patients with surgically-
resected NSCLC.
Keywords: non-small cell lung cancer, Surgical resec-
tion, survival, tobacco control and cessation
Methods: We examined all patients who had a curative-
intent NSCLC resection from 2009-2016 in 4 contiguous
Dartmouth Hospital Referral Regions of the US. We
compared patient and clinical characteristics among
P1.01-022
never, former (stopped ꢀ1 year prior), and active Smoking Cessation Related to Lung
smokers using the Chi-square and ANOVA tests. Survival Resection
analyses were conducted with the Kaplan-Meier method
Topic: Protective Factors, Risk Reduction,
Smoking Cessation
and Cox Proportional Hazards models.
Results: Of 2,202 patients, 206 (9%) were never, 846
(
38%) were former, and 1,150 (52%) were active
1
1
1
Bruno Sarana, Indrek Benno, Piret Kibur,
smokers. Significant demographic and clinical differ-
ences between cohorts included age, sex, race, insurance,
comorbidities, pulmonary function, method of detection,
ASA status, extent, primary site and length of resection,
histology, and histologic grade (all pꢁ0.05). Short-term
post-operative mortality (at 30-, 60-, 90-, 120-days)
2
2
3
Ragnar Toomas Kibur, Triin Kütt, Mait Raag,
1 1
Tanel Laisaar Thoracic Surgery Department,
2
Tartu University, Tartu/Estonia, Tartu University,
3
Tartu/Estonia, Public Health, Tartu University,
Tartu/Estonia
rates for never smokers were 1%, 2%, 4%, 4%; for active Background: Smoking cessation interventions are often
smokers, 4%, 6%, 7% and 8%; and for former smokers, ineffective, although negative health effects of smoking

S462
Journal of Thoracic Oncology Vol. 12 No. 1S
are well established. However, evidence suggests that Background: The association between cigarette
diagnosis of a severe medical condition or a surgical smoking and lung cancer mortality is well known.
intervention may force people to quit smoking without Some studies have shown a decreased overall sur-
any counseling. Aim of this study was to determine the vival (OS) in early stage non-small cell carcinoma
smoking cessation rate among patients undergoing lung (NSCLC) patients that continue to smoke after diag-
resection and factors associated with perioperative nosis. It is documented that in patients with
smoking cessation.
metastatic disease, continued smoking increases
resistance to systemic therapies but the impact of
smoking cessation during treatment on outcomes for
these patients is not well defined. Objective: To
evaluate the impact of smoking cessation, before
initiation of chemotherapy (CT), on survival in
advanced NSCLC.
Methods: All lung resection patients in one thoracic
surgery department in 6 years were included. A phone-
interview was conducted with all (accessible) patients
aged ꢀ 16. Wilcoxon rank-sum test, and chi-squared or
Fisher exact test were used for statistical analysis.
Results: In 6 years 970 patients were operated on; 406
Methods: Patients referred to our center, between
January 2010 and June 2016, and diagnosed with met-
astatic NSCLC were analyzed. Patients defined as
smokers at diagnosis and treated with at least one cycle
of chemotherapy were included. Clinical characteristics
and survival outcome were reviewed and compared
between patients who quit smoke before and after the
initiation of chemotherapy.
(
229 male, 177 female; mean age 56.4 [range 16 to 85]
years) were available for the study. At the time of sur-
gery 155 patients (38.2%) were non-smokers, 82
(
5
(
20.2%) ex-smokers, and 169 (41.6%) current smokers.
6.3% of males and 22.6% of females were smokers
p<0.0001). 145 patients had lung cancer and 261 pa-
tients other causes for lung resection, with different
smoking distribution in these 2 groups (p<0.0001).
Sixty nine patients (40.8%) quit smoking before the Results: A total of 113 patients were included [mean
operation: 22 due to the planned operation, 23 due to age 59±10 years; 89.4% (n¼101)]. The histological
the newly diagnosed disease, and 24 for other reasons. type more predominant was adenocarcinoma (70.8%)
Seventy two patients (42.6%) did not smoke after and the most common sites of metastasis were lung,
hospital discharge including 66 (39.1%) also a year bone and brain (35.4%, 23.9% and 23%, respectively).
later. An additional 40 (23.7%) patients had tried to The majority of patients had performance status 1
stop, and 57 (33.7%) continued smoking. The quit rate and no weight loss at time of diagnosis (53.1% and
was higher among lung cancer patients versus others 58.4%, respectively) and the comorbidity most preva-
(
uncorrected p¼0.007), and patients operated through lent was hypertension (19.5%). The average number
thoracotomy versus VATS (uncorrected p¼0.0295); and of cigarettes smoked was 51±23pack-years and
was not influenced by age, gender or duration of 81.4% of patients smoked >30pack-years. The most
smoking before quitting.
used CT regimen was platinum combined with peme-
trexed (63.7%). Patients who quit smoking before CT
showed a better median OS although not statistical
significant (8 vs. 7 months; p¼0.478). This was also
seen in heavy smokers ꢀ30 pack-years, with a median
OS of 8 vs. 6.5 months (p¼0.674). The multivariate
analysis only showed an influence of type of CT on
survival.
Conclusion: Almost 40% of patients undergoing lung
resection stopped smoking without special counseling,
with very few restarting. Smoking cessation rate was
higher among patients with lung cancer and patients
operated through thoracotomy.
Keywords: Smoking Cessation, Thoracic Surgery
Conclusion: Although not significant differences in OS
between groups were observed in our sample, the
median survival was better in patients that quit
smoking before the initiation of CT, even in heavy
smokers. Continued smoking after CT initiation is
known to adversely affect treatment response and
quality of life and efforts to encourage smoking cessa-
tion even among this population of patients should be
made.
P1.01-023
Smoking Cessation before Initiation of
Chemotherapy in Metastatic Non-Small
Lung Cancer: Influence on Prognosis
Topic: Protective Factors, Risk Reduction,
Smoking Cessation
Ana Linhas, Sérgio Campainha, Sara Conde,
Ana Barroso Centro Hospitalar Vila Nova de Gaia/
espinho, Vila Nova de Gaia/Portugal
Keywords: advanced NSCLC, Smoking Cessation,
chemotherapy, survival