Research paperNonpeptidic quinazolinone derivatives as dual nucleotide-binding oligomerization domain-like receptor 1/2 antagonists for adjuvant cancer chemotherapy
Graphical abstract
Introduction
Currently, immunotherapy primarily aims to artificially stimulate the immune system to improve its natural ability to stop or eliminate cancer [1]. Therefore, the identification and evaluation of novel immune targets has become an important goal of research. Because the cytosolic nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2) receptors are important components of the innate immune system, they have been pharmacologically targeted to enhance the immune response against cancer cells [[2], [3], [4], [5], [6], [7]]. Many NOD1/2 agonists have been discovered: Mifamurtide, for example, has already been approved for treating high-grade, nonmetastatic, resectable osteosarcoma after surgical excision in children to young adults [8]. However, a shift has occurred in recent with the emerging knowledge that NOD antagonists facilitate the chemotherapy of some cancers [9]. For instance, Zitvogel and coworkers have identified the NOD2 receptor as a ‘gut immune checkpoint’ based on the evidence that NOD2 curtails cyclophosphamide (CTX)-induced cancer immunosurveillance by limiting the relocation of microbes [10]. Ferri’s group demonstrated the NOD1 receptor as a putative therapeutic target in inflammation-mediated colon cancer metastasis. The experimental results revealed that NOD1 activation increased colorectal cancer cell adhesion, migration and metastasis via the p38 mitogen activated protein kinase pathway [11].
In 2011, we first reported a conjugate of paclitaxel (MTC-220, 1) and a muramyl dipeptide (MDP) derivative that was superior to PTX alone for treatment of Lewis lung carcinoma (LLC) in mice. MDP is the natural ligand for NOD2, however, we found that the prototype for MTC-220 (compound 2) is responsible for remodeling the tumor microenvironment (TME) by inhibiting NOD2 signaling and limiting PTX-induced cancer immunosurveillance in mice [12,13]. In addition, conjugates (3 and 4) of docetaxel (DTX) and MDP derivatives were designed as another chemical class of NOD1 antagonists for breast cancer treatment [14]. Effective antagonists for cancer adjuvant treatment should therefore antagonize both NOD1 and NOD2 signaling. Pharmacologically targeting both the NOD1 and NOD2 signaling pathways is expected to have a broad therapeutic utility for cancer treatment. Small molecules quinazolinones (5) and 2-aminobenzimidazoles (6) were discovered and identified as NOD1 antagonists in 2011 and 2014, respectively [[15], [16], [17]]. The NOD2 selective antagonist (7) is an imidazole derivative that was disclosed via high-throughput screening [18]. Jakopin’s group reported in 2016 a dual NOD1/2 antagonist (Fig. 1, 8) based on an indole scaffold [19,20]. Compound 9 was the first dual NOD1/2 antagonist based on a 1,4-benzodiazepine-2,5-dione derivative which sensitized chemotherapy with PTX to LLC in animals [21]. In this article, we perform the synthesis and evaluation of quinazolinone derivatives aiming to identify novel NOD1/2 dual antagonists. We have demonstrated compound 36b as a novel NOD1/2 dual antagonist that can significantly sensitize B16 tumor-bearing mice to PTX treatment.
Section snippets
The discovery of quinazolinone analogues 14 via screening
Initially, we performed a screening of a small quinazolinone library (approximately 50 compounds) that was previously established by our group aiming to identify novel NOD1/2 antagonists [22]. The library included fused-quinazolinone compounds (10, 11), spiro-quinazolinone compounds (12) and other structurally diverse quinazolinones with different substitutions at the C2 position (13–15) (Fig. 2). All the compounds were tested at a concentration of 5 μM. The results revealed that compounds 10–13
Conclusions
In summary, two hit derivatives discovered by the screening of a quinazolinone focused library were found to show potential NOD1/2 antagonistic activities. Structural and metabolic site modifications led to the discovery of a dual NOD1/2 antagonist 36b with its ability in significant improvement in terms of therapeutic efficacy in B16-bearing mice compared with PTX treatment alone. These results enrich the number of lead compounds in antagonizing NOD1/2 signaling for adjuvant cancer
General
THF, MeOH, DCM and other commercial reagents were purchased from domestic corporations and used without further purification. Silica gel for column chromatography and analytical thin layer chromatography (TLC) plates were phased from Qingdao Haiyang Chemical and Special Silica Gel Co, Ltd. The automatic LC-MS analysis was also performed on a Waters SQ Advantage mass spectrometer equipped with an UPLC system and an eluent splitter (5% eluent was split into the MS system). High-resolution LC-MS
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We gratefully acknowledge the funding support of grants from the National Natural Science Foundation of China (Grants 81803358, 81703329, 81273364 and 81773114) and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019-RC-HL-008).
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These authors contributed equally.