Identification of N-benzothiazolyl-2-benzenesulfonamides as novel ABCA1 expression upregulators

Abstract

A series of N-benzothiazolyl-2-benzenesulfonamides were designed and synthesized as novel ABCA1 expression upregulators.

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“… 271 , 336 , 352 , 379 - 382 The cholic acid analog 14b, 336 the thiophene derivative CL2-57, 271 as well as derivatives of N-benzothiazolyl-2-benzenesulfonamide, 379 ginsenoside, 352 and rutaecarpine, 367 all induced ABCA1 / Abca1 mRNA 336 , 352 , 381 and ABCA1 protein 271 , 336 , 379 , 381 content in vitro 271 , 336 , 379 and in vivo , 271 targeting the LXR-α/LXR-β pathway 352 by activation 271 or induction 336 of LXR-α/ LXRA / Lxra and/or LXR-β/ LXRB / Lxrb . In vitro , cholesterol efflux increased 379 , 381 and intracellular cholesterol as well as lipid content were reduced, 336 , 352 while plasma and liver triglycerides levels were reduced in vivo in high fat diet-fed C57BL/6 mice. 271 Interestingly, 14b induced farnesoid-X-receptor (FXR) transcription ( Fxr ), 336 and CL2-57 inhibited RXR-β, PPAR-γ, and PPAR-δ, 271 …”

“…Such synthetic approaches should be highlighted, 271 , 336 , 352 , 379 - 382 as chemical derivatization of ABCA1 inducers and elucidation of their structure-activity relationships (SAR) have not yet been comprehensively assessed. More reports are needed to gain innovative molecules that can be considered clinically for the treatment of various ABCA1-related diseases.…”

“… 136 Notably, radiolabeled substrates are very effective in terms of accurate tracing of protein function, as these molecules are not changed in their molecular integrity in contrast to fluorescence probes. 171 , 201 , 238 , 251 , 252 , 254 , 256 , 258 , 261 , 271 , 282 , 308 , 319 , 321 , 330 , 332 , 335 , 342 , 360 , 379 , 389 , 390 , 392 , 397 , 402 , 406 , 455 , 456 , 468 , 514 - 518 On the downside, conducting these experiments is constrained to regulatory requirements and requires extensive staff training as well as expensive safety measures and laboratory equipment.…”

“…Regarding fluorescent derivatives of cholesterol and phospholipids, two major types can be differentiated: (i) 7-nitro-2,1,3-benzooxadiazole (NBD) derivatives 201 , 251 , 252 , 254 , 256 , 258 , 261 , 308 , 335 , 342 , 360 , 379 , 389 , 390 , 392 , 394 , 397 , 402 , 406 , 408 , 468 and (ii) 4,4-difluoro-4-bora-3a,4a-diaza- s -indacene (BODIPY) derivatives. 271 , 282 , 319 , 321 , 330 , 332 , 455 , 456 , 515 - 517 Other fluorophore-labeled dyes have been reported, too, including the sterane analog dansylestramustine, 171 , 238 , 518 and propargyl choline, which is processed in vitro into propargylated phospholipids.…”

“…Besides qPCR and western blotting, ABCA transporter expression was reported in several studies using fluorimetric assays. This was accomplished with either (i) green fluorescent protein-(GFP)- tagged/labelled ABCA transporters 235 , 241 , 261 , 275 , 386 , 422 , 464 , 504 or (ii) luciferase promotor-(LUC)-transfected 271 , 309 , 319 , 352 , 367 , 379 , 381 , 405 , 406 , 419 , 436 , 447 ABCA transporter cells in luciferase reporter gene assays.…”