Design, synthesis and biomedical evaluation of mostotrin, a new water soluble tryptanthrin derivative

Abstract

Mostotrin (MT), a novel compound, at least five orders of magnitude more soluble in water than its mother substance, was designed and synthesised from tryptanthrin (TR). Its structure was established by nuclear magnetic resonance and mass spectrometry data and confirmed by X-ray analysis, revealing that MT is a pentacyclic product with an additional pseudo-cycle formed with the participation of one intramolecular hydrogen bond. Antimicrobial activity and cytotoxic action against tumour cells in vitro, as well as anti-tumour effects, acute toxicity and anti-inflammatory activities in vivo, were evaluated. Antimicrobial properties of MT against Mycobacterium spp and Bacillus cereus ATcc 10702 appeared to be the same as that of TR, but against the other strains used it was weaker. Furthermore, MT exhibited 5-10 times higher cytotoxic activities against tumour cell lines HcT-116, МСF-7 and K-562 than TR, but was less toxic than TR (Ld 50 of MT was 375 mg/kg, while Ld 50 for TR was 75 mg/kg). Additionally, compounds MT and TR were studied in dNA binding tests. The quenching of its fluorescence on addition to DNA solution established MT to be capable of binding to dNA. Its anti-tumour action in vivo on mice with the ascitic form of Ehrlich carcinoma was promising, particularly with joint application of MT and the antitumour drug doxorubicin. In this model, the survival and life span for the doxorubicin and 1 co-treatment group were significantly higher compared to doxorubicin treatment alone. The compound MT showed a lower immunosuppressive effect than TR at the early stages of inflammation induced in mice by LPS from E. сoli (MT hardly inhibited the release of IL-1, IL-2, or INF-γ). These results demonstrated that MT is a perspective hit compound for drug development. In our opinion, further evaluation on the biological effects of MT and its synthetic analogues could lead to safer and more effective anti-tumour and anti-tuberculosis agents than TR itself. MT has also the prospect of application in combination with known anti-tumour drugs for the treatment of oncological diseases.

Identification of Mutations Conferring Tryptanthrin Resistance to Mycobacterium smegmatis

“…Tryptanthrins attracted attention as potential anti-tuberculosis drug candidates due to their high in vitro activity against both drug-susceptible and MDR M. tuberculosis strains, and their low toxicity [ 18 , 23 , 37 ]. InhA was suggested as the target of tryptanthrins by in silico modeling [ 19 ], making it a promising alternative to isoniazid, able to overcome drug resistance provided by katG mutations [ 22 ].…”

Comparative Study of the Pharmacological Properties of Luteolin and Its 7,3′-Disulfate

“…When testing the antitumor activity of the studied substances, Ehrlich ascites and solid tumor were used, transplanted into a pathogen-free line of CD-1 mice weighing 21 ± 2 g (8 individuals in each group). Transplantation, the maintenance of strains and evaluation of the results obtained were carried out as described previously [ 44 , 45 ]. The treatment of animals with tumors was started one day after the transplantation of 3 × 10 6 ascites or 5 × 10 6 tumor cells, respectively.…”

Triptantrina: da Natureza ao Laboratório

“…A triptantrina também foi identificada, no extrato de índigo naturalis, como o composto com maior efeito antiproliferativo em cinco tipos de células identificadas em lesões de psoríase [34], e revelou ser um agente antimicótico eficaz como adjuvante e para a prevenção de reinfeções fúngicas [35]. Foi também sintetizado um novo derivado da triptantrina mais solúvel em água, o mostotrin, que demonstrou ter capacidades promissoras como agente antimicrobiano e antitumoral [36]. A triptantrina e doze novos derivados revelaram ter elevada dupla potência inibitória da indolamina 2,3-dioxigenase 1 (IDO1) e da triptofano 2,3-dioxigenase (TDO), promissores alvos no desenvolvimento de novos fármacos devido ao seu potencial no tratamento de patologias como o cancro e doenças neurodegenerativas [37].…”