Design, Synthesis and Antifungal Activity of Benzofuran and Its Analogues

Article abstract of DOI:10.1002/cjoc.201900304

Benzofuran has antifungal activity as the inhibitor of N-myristoyltransferase. Twenty-nine novel benzofuran-semicarbazide hybrids were designed and synthesized by principle of drug combinationatory. On this basis, the benzofuran ring was simplified to a resorcinol structure, and sixteen novel 1,3-dialkoxybenzene-semicarbazide hybrids were designed and synthesized. All structures of the target compounds were characterized by HRMS and NMR. The in vitro antifungal activity of target compounds was evaluated using the microdilution broth method against eight strains of pathogenic fungi with fluconazole as positive control. According to the results of the target compounds, structure-activity relationship (SAR) is summarized. The inhibitory activity against the tested strains of simplified compounds (K01—K16) has different levels improvement compared with compounds Z01—Z29. K01—K16 showed significant antifungal activities against A. fumigatus, C. kruseii, and sensitive C. albicans 5314. Notably, compounds Z20, Z22, K10, K11 and K16 also displayed different activities against two fluconazole-resistance strains that were isolated from AIDS patients. The minimal inhibitory concentration (MIC) values against fluconazole-resistant strains were in the range of 2—8 μg/mL and 4—32μg/mL, respectively. Furthermore, molecular docking was performed to investigate the binding affinities and interaction modes between the target compound and N-myristoyltransferase.

Full text of DOI:10.1002/cjoc.201900304

ABSTRACT
403
59% of patients) and poor risk (4 points, 17% of patients). Two-year
OS rates were 81%, 47%, and 21%, respectively (p < 0.0001) (figure).
Conclusion: This easy-to-compute scoring index may allow the identi-
fication of groups of transformed WM patients with different out-
comes and could be used for improving treatment choices.
Keywords: diffuse large B-cell lymphoma (DLBCL); prognostic indices;
Waldenström’s macroglobulinemia (WM).
after hybridization to the array. Spot recognition and raw data
processing was performed using standard operating procedure
according to the IMMRay guidelines (Immunovia). Normalization and
further bioinformatic and biostatistical analysis were performed
using standard tools which includes R, Qlucore and SIMCA; and sev-
eral other in-house built softwares developed in conjunction to the
experimental platform.
Results: Preliminary results using COX regression analysis shows that,
at baseline, a signature of approximately 6-8 relevant proteins are
associated with PFS. Further investigations are needed to validate this
in an independent cohort of patients. Current investigations aim to
identify if additional prognostic and biological information related to
the treatment can be derived by comparing samples at baseline, cycle
4 and beyond.
MANTLE CELL
360
SERUM BIOMARKERS ARE ASSOCIATED
WITH TREATMENT RESPONSE IN
RELAPSED MANTLE CELL LYMPHOMA
Conclusion: We have showed that prognostic information can be
derived from serum samples collected from relapsed MCL patients. To
our knowledge, this is the first time that an antibody-based array is
used as a tool to assess the possibility of developing serum-based sig-
natures useful for treatment selection in relapsed MCL patients.
Keywords: B-cell lymphoma; immune system; mantle cell lym-
phoma (MCL).
L. Lokhande1
M. Hutchings3
M. Jerkeman5
|
V.K. Emruli1
R. Räty4
S. Ek1
|
A. Kolstad2
J.D. Rodrigues1
|
|
|
|
|
1Department of Immunotechnology, Lund University, Lund, Sweden;
2Department of Oncology, Oslo University Hospital, Oslo, Norway;
3Department of Haematology, Rigshospitalet, Copenhagen, Copenhagen,
Denmark; 4Department of Hematology, Helsinki University Central
Hospital, Helsinki, Finland; 5Department of Oncology, Skane University
Hospital, Lund, Sweden
361
HIGH VIRAL LOADS OF CIRCULATING
EPSTEIN-BARR VIRUS DNA COPY NUMBER
IN PERIPHERAL BLOOD IS ASSOCIATED
WITH INFERIOR PROGNOSIS IN PATIENTS
WITH MANTLE CELL LYMPHOMA
Introduction: Recent advances in therapeutic strategies have provided
novel treatment regimens for MCL, that until recently, was associated
with dismal prognosis of 3-5 yrs median overall survival. However,
strategies to guide patient stratification are still lacking in both diag-
nostic and relapsed setting. Non-invasive methods based on liquid
biopsies would facilitate the continuous sampling of patients over
time and identification of companion diagnostic biomarkers is
warranted. For this purpose, we have used an antibody-based plat-
form to identify serum proteins in relapsed patients that are homoge-
nously treated as per the Nordic MCL6 clinical trial (Philemon). We
hypothesize that, the platform can identify if the immune status at
treatment start can influence the response to combinatorial immune-
directed therapies. We also intend to study how treatment can influ-
ence the immune status across time.
W. Xu
L. Fan
|
X. Zhou
J. Li
|
J. Liang
|
L. Wang
|
H. Zhu
|
|
Hematology, the First Affiliated Hospital of Nanjing Medical University,
Jiangsu Province Hospital, Nanjing, China; Key Laboratory of Hematology
of Nanjing Medical University, Nanjing, China; Collaborative Innovation
Center for Cancer Personalized Medicine, Nanjing, China
Introduction: Mantle cell lymphoma (MCL) is a distinct subtype of B
cell non-Hodgkin lymphoma. No research has yet documented to
investigate the prognostic implications of Epstein-Barr virus (EBV)
infection in MCL. The objective of this study was to examine whether
EBV DNA load may influence the heterogeneity in the course of the
disease in MCL patients.
Methods: Sequential serum samples from 44 patients treated with
Lenalidomide, Ibrutinib and Rituximab (Philemon trial) were
processed on the IMMRay™ platform (Immunovia). We processed
serum samples from 4 time-points; at baseline and 12, 24 and
36 weeks of treatment which corresponds to cycle 4, 7 and 10, of
the trial. The platform, allows the analysis of 380 different epitopes
among approximately 150 unique proteins. It focuses on soluble
immune-related proteins such as cytokines, chemokines and comple-
ment factors, as well as, several cancer-related markers. In brief,
antibody fragments are produced and printed on a solid support.
Samples are biotinylated and detected using a fluorescent marker
Methods: Eighty-eight MCL patients were retrospectively enrolled in
the study. EBV DNA load was detected by real-time quantitative PCR
for quantification. The univariate and multivariate Cox proportional
hazards models were established for the estimation of prognostic
factors.
Results: Twenty-seven patients were detected positive for EBV DNA
ad the median virus titer was 1.72×104 copies/mL (range, 8.20×102
to 4.14×105 copies/mL). With a median follow-up of 39 months
(range, 9 to 120 months), patients in EBV DNA-positive group

404
ABSTRACT
displayed unfavorable progression-free survival (PFS) (P=0.012) and
overall survival (OS) (P=0.004) than patients in EBV DNA-negative
group (Figure 1). Multivariate Cox regression analysis revealed that
EBV DNA-positivity was independent risk factor for both PFS (HR,
2.04; 95% CI, 1.07 to 3.92; P=0.031) and OS (HR, 2.68; 95% CI, 1.20
to 6.00; P=0.016). Reduction in EBV copies was significantly associ-
ated with therapy-response.
between 2/2013 and 2/2019. Demographics, duration of therapy, reason
for discontinuation, overall response, survival, and toxicities were exam-
ined. The primary endpoints were progression-free survival (PFS; defined
as time from OBI start to disease progression or regimen change, death
due to MZL/MCL or last-follow-up in remission), and overall survival
using the Kaplan-Meier method. All other analyses were descriptive.
Results: We identified a total of 10 pts for the entire cohort, 6 with
MZL and 4 with MCL. The median age at start of OBI was 64 years
(Range 50-92). 80% of pts were stage 4, had a median of 2 prior ther-
apies (1 MZL patient treated frontline), median ECOG status 0, and
one MZL patient had an MYD88 mutation. One patient was rituximab
naïve, but 70% were rituximab refractory. The median number of
cycles administered of OBI was 7 (Range 1-31) respectively. 50% of
pts received OBI in combination, 3 pts with bendamustine, 1 with
chlorambucil, and 1 with ibrutinib. Overall response rate was 90%
(10% CR). Median PFS and OS were 11.5 and 13.5 months respec-
tively. Two pts progressed following OBI therapy; one patient with
MZL who subsequently was treated with ibrutinib and one with MCL
subsequently treated with venetoclax.
Conclusion: Circulating EBV DNA load in whole blood proved to be a
significant predictor of prognosis in patients with MCL, which needs
further validation in large-scale clinical studies.
Keywords: Epstein-Barr virus (EBV); mantle cell lymphoma (MCL);
prognostic indices.
362
OBINUTUZUMAB THERAPY IN PATIENTS
WITH MARGINAL ZONE AND MANTLE
CELL LYMPHOMA
M.E. Hughes
S.J. Schuster
|
C. Suen
|
E. Namoglu
A. Loren
|
|
50% of pts experienced at least one Adverse event(AE). AEs included:
Infusion related reactions (40%), thrombocytopenia (40%), diarrhea
(30%), neutropenia (20%), infection (10%). Three pts were on growth
factor during OBI administration. One patient discontinued therapy
secondarily to an infusion related reaction.
|
J. Svoboda
|
S.D. Nasta
Lymphoma Department, University of Pennsylvania, Philadelphia, United
States
Conclusions: OBI therapy was well tolerated in our cohort of MZL
and MCL pts. We observed a high ORR and durable PFS and OS
opportunity. Only two pts experienced progression following OBI
therapy, both of whom are currently controlled with novel oral agents.
The AE profile of OBI was well tolerated, with toxicities consistent
with current package labeling. Additional clinical trials and/or pooled
data from retrospective observational studies will help confirm OBI
therapy’s durable efficacy benefit for pts with MZL and low-risk MCL.
Keywords: mantle cell lymphoma (MCL); marginal zone lymphoma
(MZL); obinutuzumab.
Introduction: Obinutuzumab (OBI) is FDA approved in chronic lym-
phocytic leukemia and follicular lymphoma, with favorable efficacy
profiles noted in both settings. While there was a small subpopulation
of marginal zone lymphoma (MZL) and mantle cell lymphoma patients
(pts) in the GAUSS trial and GADOLIN/GAUGUIN trials respectively,
there is little clinical experience in using OBI in these patient
populations outside the context of a clinical trial. We describe a real
world experience of OBI use in MZL and MCL pts off clinical trial.
Methods: We conducted a retrospective cohort study of all adult pts
who received OBI for MZL and MCL at the University of Pennsylvania