New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model.

Konstantinović, J
Kiriş, Erkan
Kota, KP
Kugelman-Tonos, J
Videnović, M
Cazares, LH
Terzić, Jovanović
Verbić, TŽ
Andjelković, B
Duplantier, AJ
Bavari, S
Šolaja, BA
The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES-MNs) in a postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.
Journal of medicinal chemistry


Cyclization of RGD Peptides by Suzuki-Miyaura Cross-Coupling
Kemker, Isabell; Schnepel, Christian; Schroeder, David C.; Marıon, Antoıne; Sewald, Norbert (American Chemical Society (ACS), 2019-08-22)
Halogenated L- or D-tryptophan obtained by biocatalytic halogenation was incorporated into RGD peptides together with a variety of alkyl or aryl boronic acids. Suzuki-Miyaura cross-coupling either in solution or on-resin results in side chain-to-tail-cyclized RGD peptides, for example, with biaryl moieties, providing a new dimension of structure-activity relationships. An array of RGD peptides differing in macrocycle size, the presence of D-amino acid, N-methylation, or connectivity between the indole moiet...
Identification of small-molecule urea derivatives as novel NAMPT inhibitors via pharmacophore-based virtual screening
Ozgencil, Fikriye; EREN, GÖKÇEN; ÖZKAN, YEŞİM; GÜNTEKİN ERGÜN, SEZEN; Atalay, Rengül (Elsevier BV, 2020-01-01)
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-prophosphate (PRPP) to yield nicotinamide mononucleotide (NMN), a rate limiting enzyme in a mammalian salvage pathway of nicotinamide adenine dinucleotide (NAD(+)) synthesis. Recently, intracellular NAD(+) has received substantial attention due to the recent discovery that several enzymes including poly(ADPribose) polymerases (PARPs), mono(ADP-ribose) transferases (ARTs), and sirtuins (SIR...
Regulatory effects of alanine-group amino acids on serine alkaline protease production by recombinant Bacillus licheniformis
Çalık, Pınar; Ozdamar, TH (Wiley, 2003-04-01)
Influences of the concentration and addition time of alanine-group amino acids, i.e. alanine, leucine and valine, on serine alkaline protease (SAP) synthesis were investigated by Bacillus licheniformis (DSM 1969) carrying pHV1431::subC in a defined medium to identify the amino acids creating intracellular reaction-rate limitation in SAP production. While the precursors of alanine-group amino acids, pyruvate and alanine, did not affect SAP production considerably within the range 0-15 mM, the addition of leu...
A novel synthesis of 1,2,4-oxadiazoles and isoxazoles
KIVRAK, Arif; Zora, Metin (Elsevier BV, 2014-01-28)
A novel synthesis of 1,2,4-oxadiazoles and isoxazoles is described by utilizing the reactions between amidoximes and alpha,beta-alkynic aldehydes and/or ketones. Conjugate addition products, obtained from amidoximes and alpha,beta-alkynic aldehydes and/or ketones, afford 1,2,4-oxadiazoles and isoxazoles when treated with bases and acids, respectively. 1,2,4-Oxadiazoles can also be synthesized directly from amidoximes and alpha,beta-alkynic aldehydes in a one-pot manner under basic conditions. The reactions ...
Synthesis of new derivatives of boehmeriasin A and their biological evaluation in liver cancer
Guzelcan, Ece Akhan; Baxendale, Ian R.; Atalay, Rengül; Baumann, Marcus (Elsevier BV, 2019-03-15)
Two series of boehmeriasin A analogs have been synthesized in short and high yielding processes providing derivatives differing either in the alkaloid's pentacyclic scaffold or its peripheral substitution pattern. These series have enabled, for the first time, comparative studies into key biological properties revealing a new lead compound with exceptionally high activity against liver cancer cell lines in the picomolar range for both well (Huh7, Hep3B and HepG2) and poorly (Mahlavu, FOCUS and SNU475) diffe...
Citation Formats
J. Konstantinović et al., “New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model.,” Journal of medicinal chemistry, pp. 1595–1608, 2018, Accessed: 00, 2020. [Online]. Available: