Synthesis and Cytotoxicity of 28-Oxo-Allobetulone Derivatives
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SYNTHESIS AND CYTOTOXICITY OF 28-OXO-ALLOBETULONE DERIVATIVES
E. F. Khusnutdinova, I. E. Smirnova, and O. B. Kazakova*
28-Oxo-allobetulone derivatives that were newly synthesized or prepared earlier by modification of ring A (3- and 4-pyridylidene, furfurylidene, azepane, lactam, quinolone, spiroindole, pyrazole, isoxazole, and tetraoxane derivatives) and 3β,19β,28-oleantriol were tested in vitro for cytotoxicity against 60 cell lines of 9 human tumor types. Melanoma SK-MEL-5 and CNS SNB-75 cancer cells died in the presence of 3- or 4-pyridylidene derivatives of 28-oxo-allobetulone. 3β,19β,28-Oleantriol possessed selective cytotoxicity against CNS cancer cell line SNB-75. Keywords: triterpenoids, betulin, allobetulin, 28-oxo-allobetulone, synthesis, cytotoxicity. Allobetulin and its 28-oxo-allobetulone derivative (1) are germanicane triterpenoids, a rather rare class of natural compounds [1, 2]. Compound 1 was synthesized from betulin via a Wagner–Meerwein rearrangement in the presence of various acids [3–6]. Triterpenoids with a 19β,28-epoxy-18α-oleanane skeleton include compounds with antiulcer [7], antiviral [8–10], anti-inflammatory [7], and immunoregulatory activity [11]. Butenyl esters of 2,3-seco-2,3-di- and 3,4-seco-4(23)-en3-monoacids of allobetulin inhibited acetylcholinesterase [12]. Until recently, 19β,28-epoxy-18α-oleananes were not considered valuable agents with anticancer activity [13–16]. However, 2-aminoallobetulin was shown to possess high blocking activity for cancer cells in the cell cycle S phase and upon transitioning to the G2/M phase. It also inhibited effectively DNA and RNA synthesis at concentrations of 4.6 and 5.0 μM [17]. Modification of the triterpene skeleton 2-position was a promising direction for discovering new antitumor agents [18, 19]. A series of 28-oxo-allobetulones were synthesized by us to gather new data on the structure–activity relationship of this type of triterpenoids. Their cytotoxic activity was studied in vitro against tumor cells. 29 30
O
20 12 25
1'
O
18
26
HO
28
1
O
83%
1'
N H
O
2
O 2
4
27 5
O
24
23
1
O
e 71%
b
d
O O
3
O
2
O
O
62% 3
HN O
HO
c
2
O
16
14 9
3
a
22
HN 3
5
6
a. HCOOEt, EtOH, 40% KOH, 20°C, 1 h; b. i) NH2OH·HCl, EtOH, Δ, 5 h; ii) SOCl2, dioxane, 20°C, 1 h; c. NH2(CH2)2OH, anhydr. MeOH, Δ, 4 h; d. LiAlH4, THF, 22°C, 30 min; e. furfural, 40% KOH, EtOH, 4 h
Ufa Institute of Chemistry, Ufa Federal Research Center, 71 Prosp. Oktyabrya, Ufa, 450054, Russia, e-mail: [email protected]. Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2020, pp. 401–406. Original article submitted August 4, 2019. 0009-3130/20/5603-0465
©2020
Springer Science+Business Media, LLC
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TABLE 1. Cytotoxic Activity Test Results for 2–4, 6, and 9–15 at a Concentration of 10 μM against 60 Human Cancer Cell Lines (Cell Growth Greater Than 32%) Compound
Cell growth interval, %
Average cell growth, %
2 3 4 6 9 10
87.12–116.80 73.38–109.11 77.02–131.51 88.45–114.93 76.22–111.82 63.81–115.54
103.80 100.44 100.31 99.70 99.30
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