Polyalkoxybenzenes from Plants. 5. Parsley Seed Extract in Synthesis of Azapodophyllotoxins Featuring Strong Tubulin Destabilizing Activity in the Sea Urchin Embryo and Cell Culture Assays

Abstract

A series of 4-azapodophyllotoxin derivatives with modified rings B and E have been synthesized using allylpolyalkoxybenzenes from parsley seed oil. The targeted molecules were evaluated in vivo in a phenotypic sea urchin embryo assay for antimitotic and tubulin destabilizing activity. The most active compounds identified by the in vivo sea urchin embryo assay featured myristicin-derived ring E. These molecules were determined to be more potent than podophyllotoxin. Cytotoxic effects of selected molecules were further confirmed and evaluated by conventional assays with A549 and Jurkat human leukemic T-cell lines including cell growth inhibition, cell cycle arrest, cellular microtubule disruption, and induction of apoptosis. The ring B modification yielded 6-OMe substituted molecule as the most active compound. Finally, in Jurkat cells, compound induced caspase-dependent apoptosis mediated by the apical caspases-2 and -9 and not caspase-8, implying the involvement of the intrinsic caspase-9-dependent apoptotic pathway.

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

“…[7] The discovery and development of molecules that affect tubulin polymerization, which is the origin of microtubules, is of immense importance. [8][9][10] Molecules like colchicine (1) and combretastatin A-4 (CA-4; 2) (Figure 1) bind to tubulin thereby inhibiting its polymerization into microtubules. Due to its structural simplicity, ease of synthesis, and potent antitumor activity, this class of molecules is widely studied to find potent anticancer agents.…”

Volatile Secondary Metabolites in Cascarillo (Ocotea caparrapi (Sandino-Groot ex Nates) Dugand - Lauraceae)

“…The last compound, myristicin, a safrole derivative with a methoxy group attached at carbon 4, has interesting properties such as insecticide, wound healing, anticancer and psychodelic activities, and hepatoprotective function; and this compound has application as food flavoring. Some synthetic analogs from myristicin resulted more potent than the natural product podophyllotoxin [62][63][64][65][66][67][68][69] .…”

Earthworm, a novel in vivo system to validate antimitotic compounds

“…However, in vivo or animal cell culture-based methods are now being used to confirm the antimitotic, cytotoxic, or anticancerous activity of these compounds (Sreejaya et al, 2013). A handful of alternative animal-based in vivo methods (other than mice) have been reported using sea urchin embryos, brine shrimp, or embryos of zebra fish (Ved et al, 2010;Semenova et al, 2011;Li et al, 2012). These methods may be useful in terms of high-throughput analysis and low expense compared to methods that require an animal cell culture facility.…”