Anticancer effect and neurotoxicity of S-(+)-deoxytylophorinidine, a new phenanthroindolizidine alkaloid that interacts with nucleic acids

Abstract

Phenanthroindolizidine alkaloids are a family of plant-derived compounds with significant antineoplastic activity as well as other effects like antiamebicidal, antiviral, and anti-inflammatory activities. The specific biomolecular targets of these compounds have not yet been clearly identified. S-(+)-Deoxytylophorinidine (CAT) is a new phenanthroindolizidine alkaloid, originally extracted from the roots of Tylophora atrofolliculata and Tylophora ovata. Potent anticancer activity was observed in vitro and in vivo. Neurotoxicity of CAT was also studied and it was far less serious than that of vinblastine. Interactions between this compound and DNA had been studied in detail in our laboratory previously, and we further studied its interactions with RNA.

Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

“…Since 1 was confirmed to interact with DNA and RNA [28], [29], what will happen to the down-stream cellular processes? Based on previous reports that PI3K and MAPK signaling transduction pathways played a fundamental role in the apoptosis induced by DNA-damaging drugs, we investigated the influence of deoxytylophorinine derivatives on these two signaling transduction pathways.…”

“…1 could interact with DNA and RNA and concomitantly block the process of transcription to produce the anticancer effects in Liu's research [28], [29]. And high concentrations of 1 could induce cell apoptosis (Figure S1).…”

“…Liu et al [29] discovered that this compound could penetrate the blood brain barrier and distribute in brain tissues without obvious CNS toxicity. Further study confirmed that 1 could interact with DNA and RNA dose-dependently and preferred to intercalate into AT-repeated base pair in double-helical DNA sequences.…”

Biologically active indolizidine alkaloids

“…In other studies, the trimethoxy indolizidine alkaloid designated CAT ( 18 , Figure 5A; (+)‐13a‐( S )‐deoxytylophorinidine) exerted significant antitumor activity in vitro and in vivo 60,61 . In addition, PF403 ( 19 , Figure 5A; 3‐ O ‐desmethyl‐13a‐( S )‐deoxytylophorinidine), one of three monodesmethyl metabolites of 18 , showed stronger antiproliferative activity than the parent compound or the other two metabolites in several tumor cell lines 62 .…”

Development and validation of a liquid chromatography–tandem mass spectroscopy method for simultaneous determination of (+)-(13aS)-deoxytylophorinine and its pharmacologically active 3-O-desmethyl metabolite in rat plasma

“…The anti-tumor activity of CAT is primarily attributed to its ability to intercalate into AT-repeated base pairs in double-helical DNA sequences. Further studies have shown that CAT potently suppresses the proliferation of common cancer cell lines such as HepG2 and A549 cells, with an IC 50 of approximately 10 −7 mol/L [11,12]. CAT was susceptible to metabolism by rat liver microsomes and its three major monodesmethyl metabolites were synthesized recently [13], among which 3-O-desmethyldeoxytylophorinine (S-4, Fig.…”