Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions

Abstract

Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC50 7.4 ± 0.7 μM) and colon cancer HT29 (IC50 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC50 6.0 ± 1.1 μM; HT29: IC50 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC50 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation.

Unusually cyclized triterpenoids: occurrence, biosynthesis and chemical synthesis

“…In addition, some triterpenes have illustrated enzymatic effects and have been shown to modulate specic receptor functions. [4][5][6][7] The large majority of triterpenoids are 6-6-6-5 tetra-cycles, 6-6-6-6-5 pentacycles, or 6-6-6-6-6 pentacycles and these compounds are biosynthetically formed via cascade cyclizations and rearrangements of either squalene (S) or 2,3-oxidosqualene (OS). Although the majority of the triterpenes contain tetra-or pentacyclic skeletons, together with these triterpenes derived from cyclization processes there are a number that deviate from these mainstream polycyclization of S and OS to tetra-or pentacyclic compounds which have been reported from Nature.…”

“…In addition, some triterpenes have illustrated enzymatic effects and have been shown to modulate specific receptor functions. 4–7…”

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

“…Isocyanide-based multicomponent reactions, including the Ugi four-component reaction (U4CR) [15], are among the brightest examples of MCRs, demonstrating a high degree of diversity of molecular products and universality of application in combinatorial chemistry and especially in drug discovery [16,17]. The possibility of using the U4CR for the synthesis of important cytotoxic agents that cause necrosis of cancer cells through apoptosis from terpene and steroid derivatives was shown [18]. For example, Molbank 2023, 2023, M1707 2 of 5 ecdysteroid peptides obtained via the U4CR from 6-amino-20-hydroxyecdysone exhibited cytotoxic activity against leukemia T-cells [19].…”

Editorial to Special Issue “Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery”

“…Notably, these MCRs have great potential in Medicinal Chemistry in order to establish lead compounds in a short period of time as well as on an industrial scale. The Westermann group [ 1 ] has employed MCRs, in particular the Ugi-four component reaction (U-4CR), to prepare semi-synthetic analogs of triterpene acids (betulinic acid and fusidic acid), and steroids (cholic acid) conjugated with TEMPO (nitroxide). Notably, the nitroxide labelled betulinic and fusidic acid derivatives illustrated much better cytotoxic effects on prostate cancer (PC3) and colon cancer (HT29).…”