Modification of N-(6-(2-methoxy-3-(4-fluorophenylsulfonamido)pyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide as PI3Ks inhibitor by replacement of the acetamide group with alkylurea
Graphical abstract
A series of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)urea derivatives were synthesized and evaluated to discover anticancer agents with low toxicity.
Introduction
The chemical and biological study of heterocyclic compounds has been an interesting field in medicinal chemistry for a long time. [1,2,4]triazolo[1,5-a]pyridine consists of a triazole ring fused with a pyridine ring. There are hydrogen bond acceptors and hydrogen bond donor in the structure of 2-acetylmino-[1,2,4]triazolo[1,5-a]pyridine. Thus, the structure is considered as an ideal fragment or a scaffold in drug design. The derivatives of [1,2,4]triazolo[1,5-a]pyridine exhibit a broad spectrum of biological activities such as anticancer, anti-inflammatory, antimicrobial and antidiabetic activity. CEP-33779, possessing the scaffold of 1,2,4-triazolo[1,5-a]pyridine, was discovered as a novel, selective, and orally bioavailable JAK2 inhibitor and can be used for cancer therapy or rheumatoid arthritis treatment.1, 2, 3 2-Acylamino-6-aryl-[1,2,4]triazolo[1,5-a]pyridines were identified as inhibitors of the leishmania cdc 2-related protein kinase CRK3 and may be used to treat tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT).4 PI3Kγ plays a key role in innate immune responses such as immune cell migration.5, 6 CZC19945 and CZC24832, derived from 6-aryl-[1,2,4]triazolo[1,5-a]pyridine, were identified as PI3Kγ inhibitors with good in vivo PK profile and efficacy in vitro and in vivo models of inflammation.7 Further, CZC24832 was proved to be efficacious in regulate interleukin-17-producing T helper cell (TH17) differentiation and may be of use for the treatment of autoimmune and inflammatory disorders.8 Recently, a series of 2-ureido-[1,2,4]triazolo[1,5-a]pyridine derivatives were synthesized and two compounds exhibited excellent PI3Kγ/δ potency with high selectivity over the other isoforms and the general kinome.9 In addition, multisubstituted [1,2,4]triazolo[1,5-a]pyridines were discovered as inhibitors of β-1,6-glucan synthesis with potent antifungal activity.10 2-Ureido-5,7-disubstituted-[1,2,4]triazolo[1,5-a]pyridine was reported as good antibacterial agent with potent Gram-positive antibacterial activity.11 Early, 6-substituted [1,2,4]triazolo[1,5-a] pyridine was reported as a potent DPP-4 inhibitor and may be used to treat type 2 diabetes.12
Both PI3K (a family of lipid kinase) and mTOR (mammalian target of rapamycin) have been found to play key regulatory roles in many cellular processes, including cell growth, proliferation, differentiation, motility and survival.13 Accumulation evidence supports the notion that The PI3K/AKT/mTOR signal transduction pathway is dysregulated expression in many cancers, contributing to cellular transformation and tumor growth.14 Therefore, PI3Kα and mTOR, as key nodes of the PI3K/AKT/mTOR pathway, have been identified as promising kinase targets for cancer therapy.15, 16 Recently, several PI3K inhibitors and PI3K/mTOR dual inhibitors have been in clinical development.17, 18 Among the reported PI3K/mTOR dual inhibitors, N-(5-(quinilin-6-yl)-pyridin-3-yl)phenylsulfonamide derivatives are a class of PI3K/mTOR dual inhibitors with potent anticancer activity in vitro and in vivo. Two ring nitrogen atoms in pyridine and quinoline are the main components of pharmacophore. GlaxoSmithKline discovered GSK212645819 (Fig. 1) as a potent, orally bioavailable PI3Kα and mTOR dual inhibitor. Amgen Inc. designed, synthesized and evaluated several classes of N-(2,5-disubstituted-pyridin-3-yl)phenylsulfonamides, and discovered that N-(2-chloro-5-(4-morpholinoquinilin-6-yl)pyridin-3-yl)-4-fluorophenylsulfonamide,20 N-(2-chloro-5-(2-acetylaminobenzo[d]thiazol-6-yl)pyridin-3-yl)-4-fluorophenylsulfonamide21 (compound A, Fig. 1) and N-(2-chloro-5-(2-acetylamonoimidazo[1,2-b]pyridazin-6-yl)pyridin-3-yl)-4-fluoro phenylsulfonamide22 are excellent PI3K/mTOR dual inhibitors and anticancer agents. According to the X-ray cocrystal structure of PI3Kγ with GSK2126458,19 we proposed that the structure of an amide group may take the place of the water molecule bridge. Thereupon, we synthesized a series of 2-substituted-3-phenylsulfonylamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides and discovered that the designed compounds are novel PI3K inhibitors and anticancer agents.23 Thereafter, we combined the benzamide moiety with 2-aminobenzothiazole to discover novel anticancer agents.24 Recently, it has been reported that PI3K/mTOR dual inhibitor VS-5584 can preferentially targets cancer stem cells.25 This discovery may potentially bring a breakthrough to the treatment of cancer. Thus, developing new PI3K/mTOR dual inhibitors is still needed.
In an attempt to develop novel anticancer agents, we combined 2-acetylamino-[1,2,4]triazolo[1,5-a]pyridine with N-pyridin-3-ylphenylsulfonamide to synthesize a series of [1,2,4]triazolo[1,5-a]pyridinylpyridines and the anticancer effects of the synthesized compounds were evaluated in vitro and in vivo. Therefore we discovered that compound B (Fig. 1) displayed potent antiproliferative activities in vitro and remarkable anticancer effects in vivo.26 However, the body weight of mice dropped below 90% of the starting body weight over the course of oral administration at 5 mg/kg, which indicated that compound B displayed some toxicity. Therefore, the toxicity of compound B caught our attention.
To reduce the toxicity and retain the anticancer effect of compound B, we intend to replace the 2-acetylamide in compound B with chain-extended urea to search for the novel anticancer agents with low toxicity (Fig. 2). In this paper, we reported our studies on the synthesis, biological activities evaluation of a series of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)urea derivatives.
Section snippets
Chemistry
The synthetic route of compounds 1a–1q is outlined in Scheme 1. 6-Bromo-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine was reacted successively with CDI (N,N’-carbonyldiimidazole) and amine to yield intermediates 2a–2l. In the case of preparing 2l, glycine ethyl ester was used as an amine. The ester group in intermediate 2l was hydrolyzed to afford the carboxylic acid 2m, which was subsequently condensed with pyrrolidine, piperidine or morpholine to produce intermediates 2n–2p. The phenylsulfonamides
Antiproliferative activities in vitro
We first evaluated the antiproliferative activities of the synthesized compounds against human colon carcinoma cell line (HCT-116, PI3CA, mutant: H1047R), human breast adenocarcinoma carcinoma cell line (MCF-7, PI3CA, mutant: E545K), glioma cell line (U87 MG, PTEN null) and lung adenocarcinoma epithelial cell line (A549, KRAS mutant) by applying the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay. The PI3K and mTOR dual inhibitor BEZ235 was used as the
Conclusions
In present study, a series of 1-alkyl-3-(6-(5,6-disubstitutedpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)urea derivatives were synthesized and characterized. Their antiproliferative activities in vitro were evaluated via MTT assay against four cancer cell lines including HCT-116, MCF-7, U87 MG and A549. The SAR of the title compounds was discussed. Compounds 1c and 1e were tested for their inhibitory activity against PI3Ks and mTOR. Meanwhile, the acute oral toxicity of four compounds was
Chemistry
Unless specified otherwise, all the starting materials, reagents and solvents were commercially available. All the reactions were monitored by thin-layer chromatography on silica gel plates (GF-254) and visualized with UV light. All the melting points were determined on a Beijing micro melting-point apparatus and thermometer was uncorrected. NMR spectra were recorded on a 400 Bruker NMR spectrometer with tetramethylsilane (TMS) as an internal reference. All chemical shifts are reported in parts
Acknowledgment
Financial support from National Natural Science Foundation of China (Grant Nos. 21072156 and 81272448) is gratefully acknowledged.
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2019, European Journal of Medicinal ChemistryCitation Excerpt :Compounds with 2-methoxy-3-(4-fluorophenylsulfonamino) pyridine motif attached at position-6 of 1,2,4-triazolo[1,5-a]pyridine was crucial for in-vitro cytotoxic activity. The compound 56 was found to have significant inhibitory activities with IC50 values 0.13 μM, 0.21 μM, 0.56 μM and 0.42 μM against HCT-116, MCF-7, U87 MG and A549 cell lines [93]. Shao et al. synthesized a series of 2-substituted-3-sulfonamino-5-(morpholinoquinazolin-6-yl)benzamides and 2-methoxy-3-sulfonamino-5-(4-morpholinoquinazolin-6-yl)benzamides and studied their in-vitro anticancer activities against four human cancer cell lines- A549, HCT-116, U87 MG and KB.
Synthesis of a novel family of water-soluble 2H,3H-[1,3]thia- and -selenazolo[3,2-a]pyridin-4-ium heterocycles by annulation reactions
2019, Tetrahedron LettersCitation Excerpt :The course of this reaction is determined by high halophilicity of the tellurium atom. It is known that diorganyl tellurides are used as dehalogenation reagents [15]. This property was manifested, for example, in the reactions of divinyl and diallyl tellurides with selenium dichloride and dibromide leading to the halogenation of the tellurium atom and the formation of divinyl and diallyl tellurium dihalides in high yields [16].
Synthesis and antiproliferative evaluation of novel 1,2,4-triazole derivatives incorporating benzisoselenazolone scaffold
2016, Bioorganic and Medicinal Chemistry LettersEfficient and selective syntheses of novel unsaturated chalcogen-containing pyridine derivatives
2016, Tetrahedron LettersCitation Excerpt :The development of pyridine derivatives bearing organochalcogen functions is still an important task. Previously, we have developed a number of methods for the preparation of vinylic chalcogenides using various reactions8,9 and especially by the nucleophilic addition of organochalcogenolate and chalcogenide anions to triple bonds.9 Previously, we reported the reaction of 2-pyridinylselanyl bromide with divinyl selenide, leading to the annulated heterocycle 3-(vinylselanyl)-2,3-dihydro[1,3]selenazolo[3,2-a]pyridin-4-ium bromide (Scheme 1).10
Synthesis and anticancer effects evaluation of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol-2-yl)urea as anticancer agents with low toxicity
2015, Bioorganic and Medicinal ChemistryCitation Excerpt :In our previous work, we combined the benzamide moiety with 2-aminobenzothiazole to discover novel anticancer agents (strategy A in Fig. 2).25 Recently, we discovered that 1-alkyl-3-(6-(2-methoxy-3-(4-fluorophenylsulfonylamino)pyridine-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)urea derivatives can serve as potent PI3K inhibitors and anticancer agents with low toxicity.26 In this work, we intend to replace the 2-acetylamino moiety in compound A with alkylamino or alkylurea moiety to search for the novel anticancer agents with low toxicity (strategy B in Fig. 2).