The title drug delivery compounds with pharmacophoric moieties were synthesized, and their interaction with model biomembranes (dipalmitoylphosphatidylcholine vesicles) was examined. © 2014 Mendeleev Communications. All rights reserved

Dzyurkevich M.

Faizullin D.

Plemenkov V.

Stoikov I.

Timofeeva K.

Zuev Y.

Mendeleev Communications

Kazan Federal University Digital Repository

Mendeleev Commun., 2014, 24, 224–225– 224 –© 2014 Mendeleev Communications. All rights reserved.MendeleevCommunicationsTargeted drug delivery is of major current interest to medicine, specifically in oncology.1,2 The design of drugs capable of crossing cell membranes is the main problem in this field.3 The current synthesis of pharmacologically active compounds involves the formation of hybrid molecular structures4,5 or molecular con­jugates6–11 with different combinations of pharmacophoric func­tions and properties.12,13Amphiphilic compounds with spatially separated hydrophilic and lipophilic fragments tend to exhibit membranotropic activity. Thus, there are great prospects in the modification of natural pro­ducts, especially isoprenoids.14–16 Furthermore, isoprenoid hydro­ carbon frame structures have found application as membrane anchors in the design of modulators for membrane­integrated proteins.17,18 Therefore, we hypothesized that the introduction of bio­logically active fragments into terpenoid hydrocarbon structures may lead to their targeted delivery into subcellular compartments. To verify this hypothesis, we synthesized amphiphilic compounds containing a terpenoid hydrocarbon chain. Our aim was to deter­mine how different hydrophilic fragments in terpenoid derivatives affect their ability to interact with a phospholipid membrane. Based on monoterpene b­myrcene, we prepared compounds con­taining carboxyl (2), carboxylate (3) and tertiary ammonium (6) groups using the Diels–Alder click reaction between N­sub sti­tuted maleimides 1 and 5 and b­myrcene (Scheme 1).†Amphiphilic adducts of myrcene and N-substituted  maleimides as potential drug delivery agents Mikhail S. Dzyurkevich,a Kseniya N. Timofeeva,a Dzhigangir A. Faizullin,b  Yuri F. Zuev,a,b Ivan I. Stoikov*a,b and Vitaly V. Plemenkovca A. M. Butlerov Institute of Chemistry, Kazan (Volga Region) Federal University, 420008 Kazan, Russian Federation. Fax: +7 843 233 7416; e-mail: Ivan.Stoikov@mail.rub Kazan Institute of Biochemistry and Biophysics, Kazan Scientific Center of the Russian Academy of Sciences, 420111 Kazan, Russian Federationc Institute of Biochemistry, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russian Federation06.012DOI: 10.1016/j.mencom.2014.The title drug delivery compounds with pharmacophoric moieties were synthesized, and their interaction with model biomembranes (dipalmitoylphosphatidylcholine vesicles) was examined.† 2-[5-(4-Methylpent-3-en-1-yl)-1,3-dioxo-3a,4,7,7a-tetrahydro-1H-iso-indol-2(3H)-yl]acetic acid 2. Imide 1 (0.20 g, 1.3 mmol) was dissolved in 5 ml of THF. Then 0.34 ml (2.0 mmol) of myrcene was added to this solu tion. The mixture was left overnight at room temperature. There after, THF was removed in a vacuum and the solid residue was recrys tallized from n­hexane to yield 0.28 g (74%) of compound 2, mp 84­85 °C. 1H NMR (CDCl3) d: 1.59 (s, 3 H, Me), 1.68 (s, 3 H, Me), 2.03 (m, 4 H, CH2), 2.26 (m, 2 H, CH2), 2.56 (m, 2 H, CH2), 3.17 (ddd, 2 H, CH, 3JHH 9.2 Hz, 3JHH 6.3 Hz, 3JHH 3.4 Hz), 4.25 [s, 2 H, C(O)CH2N], 5.03 (br. s, 1H, =CH), 5.57 (br. s, 1H, =CH). 13C NMR (CDCl3) d: 17.7, 24.0, 25.7, 25.9, 27.5, 37.2, 39.2, 39.5, 39.8, 119.8, 123.6, 131.9, 140.2, 171.5, 179.2, 179.4. IR (n/cm–1): 1748, 1676 (C=O), 2728, 2601, 2520 (COOH). MS (MALDI­TOF), m/z: 291.9 [M + H]+, 313.8 [M + Na]+ (calc. for [M+], m/z 291.2). Found (%): C, 65.72; H, 7.07; N, 5.10. Calc. for C16H21NO4 (%): C, 65.96; H, 7.27; N, 4.81. Sodium 2-[5-(4-methylpent-3-en-1-yl)-1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl]acetate 3. Sodium (0.1 g, 4.30 mmol) was added  to the solution of compound 2 (0.10 g, 0.34 mmol) in 5 ml of abs. THF. The mixture was stirred for 6 h and then filtered. The filtrate was evaporated and solvent traces were removed in a high vacuum. Yield of compound 3 NOONEt2 NOONEt2I–NOOCOOHNOOMeMe415iiiiNOOMeMe62  R = HCOOR3  R = NaiiMeNEt2MeI–iScheme 1 Reagents and conditions: i, b­myrcene, THF, 12 h; ii, abs. THF, Na, 6 h; iii, MeCN, MeI, 20 °C.was 0.10 g (93%). 1H NMR (DMSO­d6) d: 1.54 (s, 3 H, Me), 1.62 (s, 3 H, Me), 1.91 (m, 4 H, CH2), 1.98 (m, 2 H, CH2), 2.16 (m, 2 H, CH2), 2.30 (m, 2 H, CH2), 3.06 (ddd, 2 H, CH, 3JHH 9.1 Hz, 3JHH 6.0 Hz, 3JHH 3.0 Hz), 3.56 (s, 2H, CH2), 4.97 (br. s, 1H, =CH), 5.47 (br. s, 1H, =CH). 13C NMR (DMSO­d6) d: 22.8, 28.7, 30.6, 30.7, 31.2, 32.2, 42.1, 43.7, 44.2, 47.7, 125.1, 129.0, 136.0, 144.6, 173.5, 184.7, 184.8. MS (MALDI­TOF), m/z: 313.8 [M + H]+, 335.8 [M + Na]+ (calc. for [M+], m/z 313.1). Found (%): C, 61.10; H, 6.34; N, 4.54. Calc. for C16H20NNaO4 (%): C, 61.33; H, 6.43; N, 4.47. N,N-Diethyl-N-methyl-2-[5-(4-methylpent-3-en-1-yl)-1,3-dioxo-3a,4, 7,7a-tetrahydro-1H-isoindol-2(3H)-yl]ethanaminium iodide 6. Myrcene (5 ml, 29.4 mmol) was added to the solution of compound 5 (0.3 g, 0.88 mmol) in 20 ml of THF. The mixture was left at room temperature for 24 h. Thereafter, THF was removed in a vacuum and the solid residue was recrystallized from ethyl acetate to yield 0.35 g (83%) of compound 6, mp 99–100 °C. 1H NMR (CDCl3) d: 1.44 (t, 6 H, Me, 3JHH 7.25 Hz), 1.58 (s, 3 H, Me), 1.66 (s, 3 H, Me), 2.00 (m, 4 H, CH2), 2.21 (m, 2 H, CH2), 2.53 (m, 2 H, CH2), 3.28 (ddd, 2 H, CH, 3JHH 9.3 Hz, 3JHH 6.9 Hz, 3JHH 2.2 Hz), 3.32 (s, 3 H, +N–Me), 3.69 (m, 6 H, +N–CH2), 3.89 (t, 2 H, CH2N, 3JHH 7.2 Hz), 5.00 (br. s, 1H, =CH), 5.53 (br. s, 1H, =CH). 13C NMR (CDCl3) d: 8.5, 17.8, 23.9, 25.7, 26.1, 27.3, 32.4, 37.4, 39.6, 40.0, 48.4, 56.7, 57.7, 120.0, 123.4, 132.1, 140.5, 179.9, 180.0, 181.7. IR (n/cm–1): 1767, 1695 (C=O). MS (MALDI­TOF), m/z: 346.7 [M – I]+ (calc. for [M+]: m/z 474.2). Found (%): C, 52.92; H, 7.32; N, 6.09; I, 26.69. Calc. for C21H35IN2O2 (%): C, 53.16; H, 7.44; N, 5.90; I, 26.75.

Amphiphilic adducts of myrcene and N-substituted maleimides as potential drug delivery agents

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Amphiphilic adducts of myrcene and N-substituted maleimides as potential drug delivery agents

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