“…Pyridine hydrochloride in DMF [ 26 ] was identified as the optimal reagent for removing the Ts group, yielding makaluvamine D ( 5 ) in a good yield. Other attempted detosylation conditions (Cs 2 CO 3 in THF/MeOH [ 27 ], NaH in DMF [ 28 ], and TFA/Me 2 S [ 29 ]) were not effective. Double N -methylation at N -1 and N -5 occurred following treatment with iodomethane in the presence of NaH, resulting in the synthesis of makaluvamine P ( 10 ) in excellent yield.…”
Makaluvamine J, a pyrroloiminoquinone alkaloid of marine sponge origin, and its analogs were synthesized and assessed for their potential to develop as a novel and selective growth inhibitor targeting human pancreatic cancer PANC-1 cells. Ts-damirone B, a common precursor featuring a pyrroloiminoquinone core structure, was synthesized through Bartoli indole synthesis and IBX-mediated oxidation. Late-stage diversification at N-5 and N-9 yielded makaluvamine J and several analogs. A structure–activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at N-9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at N-5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog 24 showed potent and selective cytotoxicity (IC50 = 0.029 µM, selective index = 13.1), exceeding those of natural products.
“…Pyridine hydrochloride in DMF [ 26 ] was identified as the optimal reagent for removing the Ts group, yielding makaluvamine D ( 5 ) in a good yield. Other attempted detosylation conditions (Cs 2 CO 3 in THF/MeOH [ 27 ], NaH in DMF [ 28 ], and TFA/Me 2 S [ 29 ]) were not effective. Double N -methylation at N -1 and N -5 occurred following treatment with iodomethane in the presence of NaH, resulting in the synthesis of makaluvamine P ( 10 ) in excellent yield.…”
Makaluvamine J, a pyrroloiminoquinone alkaloid of marine sponge origin, and its analogs were synthesized and assessed for their potential to develop as a novel and selective growth inhibitor targeting human pancreatic cancer PANC-1 cells. Ts-damirone B, a common precursor featuring a pyrroloiminoquinone core structure, was synthesized through Bartoli indole synthesis and IBX-mediated oxidation. Late-stage diversification at N-5 and N-9 yielded makaluvamine J and several analogs. A structure–activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at N-9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at N-5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog 24 showed potent and selective cytotoxicity (IC50 = 0.029 µM, selective index = 13.1), exceeding those of natural products.
“…Thus, when the derivative 4a was treated with NaH in DMF at 60°C, corresponding 1,3-di- tert -butylguanidine, (8) was isolated in 63% yield ( Scheme 4 ). 62 Scheme 4 Synthetic modification of guanidine …”
“…This study was approved by the Committee on the Ethics of Animal Experiments of Jilin Agricultural University. According to the method described by Sun et al, 15 healthy male Sprague−Dawley rats aged 7−8 weeks in the weight range of 200−220 g were obtained from Liaoning Changsheng Biotechnology Co., Ltd. (Certificate No. SXCK (Liao) 2022-0012, Shenyang, China) and housed in temperature-controlled rooms (22−25 °C) with 12 h light/dark cycles.…”
Section: Evaluation Of Qmddq Transport In An Evertedmentioning
We investigated the absorption mechanism of the shrimp peptide QMDDQ in small intestines, explored its physiological function in inhibiting neuronal hyperactivity, and verified its entry into the brain in vivo to display functional activity. The everted rat sac model and a Caco-2 paracellular absorption monolayer model were used, indicating that QMDDQ has a good absorption capacity with an apparent permeability coefficient (P app ) > 1 × 10 −6 cm/s and the absorption of QMDDQ was concentration-dependent. When the concentration of QMDDQ was 1 mM and the transport time was 180 min, the highest absorption concentration of QMDDQ was 41.17 ± 3.48 μM (P < 0.05). The myosin light-chain kinase (MLCK)-specific inhibitor ML-7 and activator MPA, Western blotting, and immunofluorescence results showed that QMDDQ absorption takes place by mediating the MLCK-p-MLCK-MLC signaling pathway, reversibly opening the zonula occludens-1 (ZO-1), occludin in tight junctions (TJs), upregulating claudin-2 expression, and reaching targets through blood to inhibit neuronal overactivity. Results of fluorescence imaging in vivo verified that QMDDQ could enter the brain 4 h after oral administration. The results provide a theoretical foundation for the mechanism of paracellular absorption of active peptides and a starting point for the development of functional foods for Alzheimer's disease intervention.
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