Abstract
In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among them, the indole derivative 3 is one of the most selective PI3Kδ inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3Kδ/γ inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in N-(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N-(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6, the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives 15a–J and 16a–d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4, these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3Kδ inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3Kγ. Moreover, the introducing of a fluorine atom at the 7-position of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3Kδ inhibitory activity. In agreement with their high PI3Kδ selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation.
Highlights
All the class I Phosphoinositide 3-kinases (PI3Ks) isoforms are implicated in mounting evidences that support a therapeutic role for inhibition of PI3Kα in diabetes [17,18], cancer [11,12,13,14,15,16]
PI3Kδ inhibitors, selectivity of the quinazolinone-based PI3Kδ inhibitors, in previous work, we introduced a pyrazolo in previous work, we introduced pyrazolo
In a continuous study to find more potent and selective PI3Kδ inhibitors based on the rotation-limiting strategy, we substituted the carbonyl in the quinazolinone core for the sulfonyl group, designed and synthesized a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives
Summary
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that regulate numerous biological functions, including cell growth, proliferation, differentiation, motility, and intracellular trafficking, through the phosphorylation of the phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the lipidMolecules 2019, 24, 4299; doi:10.3390/molecules24234299 www.mdpi.com/journal/molecules trafficking, through the phosphorylation of the phosphatidylinositol (PIP2)to of second messenger phosphatidylinositol (PIP3) [1,2,3].There are three classes the lipid phosphatidylinositol are thegeneratePI3K enzyme, ofsecond whichmessenger class I PI3Ks are the mostly studied and further divided intoThere subgroups classes of the PI3K enzyme, classI PI3Ks mostly studied andand further dividedIA three (PI3Kα, PI3Kβ, and PI3Kδ) andofIBwhich (PI3Kγ) based on are thethe signaling pathways the regulatory into subgroupsIA and IB based on the signaling pathways proteins to which they bind [4,5]. The class IA PI3K isoforms mediate the signal transductionand from the regulatory proteins to which they bind [4,5]. PI3Kα and PI3Kβ are ubiquitously expressed, while PI3Kδ and PI3Kγ are dominantly by G-protein coupled receptors [7]. All the class I PI3K isoforms are implicated in mounting evidences that support a therapeutic role for inhibition of PI3Kα in diabetes [17,18], cancer [11,12,13,14,15,16]. There are mounting evidences that support a therapeutic role for inhibition of PI3Kβ in inthrombosis [19,20], PI3Kδ and PI3Kγ in both rheumatoid and asthma [21,22,23,24], PI3Kα diabetes [17,18], PI3Kβ in thrombosis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
