Three new monoterpenoid alkaloids, melomorines A–C (1–3), along with melohemsine B (4), were isolated from the 70% ethanol extract of the aerial parts of Melodinus morsei. Structural elucidation of all the compounds was performed on the basis of spectral data. All the compounds were tested in vitro for cytotoxic activities. As a result, alkaloids 1, 2, and 4 exhibited cytotoxicities against all the five tested tumor cell lines with IC₅₀ value of less than 20 μM.

Using virtual FragLites screening and a fragment-based drug discovery (FBDD) strategy, we designed and synthesized a series of 6-substituted-1-(3,4,5-trimethoxyphe-nyl)-1H-indole derivatives as potential tubulin polymerization inhibitors. Among them, compound 3g exhibited the best antiproliferative activity within this series and affected microtubule dynamics in a concentration-dependent manner. Further studies indicated that 3g induced G₂/M cell-cycle arrest and triggered apoptosis in MCF-7 cells. In vivo, 3g achieved tumor growth inhibition rates of 23.3% and 44.2% at 20 mg/kg and 50 mg/kg, respectively, without evident systemic toxicity. These results suggest that 3g shows preliminary antitumor efficacy and may serve as a starting point for further mechanistic and structural studies. Further optimization and detailed pharmacokinetic and toxicity studies are merited to advance these inhibitors in preclinical development.

Background/Objectives: Cancer persists as a leading concern in the current medical field, and current therapies are limited by toxicity, cost, and resistance. Targeted inhibition of tubulin polymerization is considered as a promising therapeutic strategy for cancer treatment. Methods: Thirty-one new tubulin polymerization inhibitors were designed via molecular hybridization techniques, and BLI technology was employed to quantitatively investigate their interactions with tubulin. Antiproliferative activities against MCF-7, MDA-MB-231, A549, and HeLa cell lines was evaluated using the CCK8 assay. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. The anti-tumor activity of compound B6 was validated in a mouse melanoma tumor model. Results: Compounds exhibited varying degrees of antiproliferative activity against four tumor cell lines. Among them, compound B6 was the most promising candidate and displayed strong broad-spectrum anticancer activity with an average IC₅₀ value of 2 μM. The mechanism studies revealed that compound B6 inhibited tubulin polymerization in vitro, disrupted cell microtubule networks, and arrested the cell cycle at G2/M phase. Furthermore, B6 displayed significant in vivo antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 70.21% (50 mg/kg). Conclusions: This work shows that B6 is a promising lead compound deserving further investigation as a potential anticancer agent.