New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase

Abstract

The incidence of diabetes mellitus (DM), one of the most common chronic metabolic disorders, has increased dramatically over the past decade and has resulted in higher rates of morbidity and mortality worldwide. The enzyme, α-Glucosidase (α-GLy), is considered a therapeutic target for the treatment of type 2 DM. Herein, we synthesized arylidene, heterocyclic, cyanoetoxy- and propargylated derivatives of quinopimaric acid (levopimaric acid diene adduct with p-benzoquinone) 1–50 and, first, evaluated their ability to inhibit α-GLy. Among the tested compounds, quinopimaric acid 1, 2,3-dihydroquinopimaric acid 8 and its amide and heterocyclic derivatives 9, 30, 33, 39, 44, with IC50 values of 35.57–65.98 μM, emerged as being good inhibitors of α-GLy. Arylidene 1β-hydroxy and 1β,13α-epoxy methyl dihydroquinopimarate derivatives 6, 7, 26–29, thiadiazole 32, 1a,4a-dehydroquinopimaric acid 40 and its indole, nitrile and propargyl hybrids 35–38, 42, 45, 48, and 50 showed excellent inhibitory activities. The most active compounds 38, 45, 48, and 50 displayed IC50 values of 0.15 to 0.68 μM, being 1206 to 266 more active than acarbose (IC50 of 181.02 μM). Kinetic analysis revealed the most active diterpene indole with an alkyne substituent 45 as a competitive inhibitor with Ki of 50.45 μM. Molecular modeling supported this finding and suggested that the indole core plays a key role in the binding. Compound 45 also has favorable pharmacokinetic and safety properties, according to the computational ADMET profiling. The results suggested that quinopimaric acid derivatives should be considered as potential candidates for novel alternative therapies in the treatment of type 2 diabetes.

Synthesis of Novel Diterpenic Peptides via the Ugi Reaction and Their Anticancer Activities

“…The spectra were recorded at the Center for the Collective Use "Chemistry" of the Ufa Institute of Chemistry of the UFRC RAS and RCCU "Agidel" of the UFRC RAS. The 1 H and 13 C NMR spectra were recorded on a "Bruker Avance III" (Bruker, Billerica, MA, USA, 500 and 125.5 MHz, respectively, δ, ppm, Hz) in CDCl 3 , internal standard-tetramethylsilane. The mass spectra were obtained on a liquid high-resolution chromatograph-mass spectrometer Agilent LC/Q-TOF 6530 (Santa Clara, CA, USA).…”

“…The structure of the products was confirmed by NMR, IR, and HRMS spectroscopy (see Supplementary Material Figures S1 and S2). In the 13 C NMR spectra of the compounds 3 and 4, the CON-, CONH-and COO-carbon atom signals appeared at the δ 179.99/179.89, 170.13/169.67 and 169.42/169.28 ppm, respectively. The 1 H NMR spectra contained NH atom signals as broadened signals at the δ 6.69/6.65 ppm.…”

“…In addition, abietic acid and its derivatives induced overexpression of the cytochrome C protein and significantly reduced carcinogenesis and chemotherapy resistance [11]. The multidirectional biological action of abietane diterpenoids, combined with their low toxicity and polyactivity, are their important advantages in the development of drugs for the prevention and treatment of malignant tumors [12,13].…”

Inhibitory properties of quinopimaric acid derivatives towards cholinesterases

“…All the reagents and solvents were purchased from standard commercial vendors and were used without any further purification. Compounds 1-3, 11, 13 (Smirnova et al 2008), 9, 22, 23 (Tretyakova et al 2020a), 12 (Tretyakova et al 2015), 14, 16 (Tretyakova et al 2019), 15 (Tret'yakova et al 2020b), 17, 19, 20 (Shul'ts et al 2009, 18, 21, 24-28 (Tretyakova et al 2022) were obtained according to the methods described previously.…”

Novel Molecules in Diabetes Mellitus, Dyslipidemia and Cardiovascular Disease

“…Teryakova’s team carried out a very interesting study where abietane-type derivatives with arylidene, heterocyclic, nitrile, and acetylene fragments were used to inhibit the enzyme, α-Glucosidase (α-GLy); the efficacy of these novel compounds was investigated in vitro and by molecular modelling approaches. The complex investigation, that included absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling or kinetic studies of the novel synthesized compounds, led to the conclusion that a lead diterpene indole with an alkyne substituent of 45 was identified as a competitive inhibitor for the enzyme α-GLy involved in the glucose metabolism, which provides an insight into novel antidiabetic drug development [ 1 ].…”