New 2-Oxoindolin Phosphonates as Novel Agents to Treat Cancer: A Green Synthesis and Molecular Modeling

Abstract

The work reports the facile synthesis of novel α-aminophosphonate derivatives coupled with indole-2,3-dione moieties, namely the diethyl(substituted phenyl/heteroaryl)(2-(2-oxoindolin-3-ylidene)hydrazinyl)methylphosphonates derivatives 4(a–n). One-pot three component Kabachnik-Fields reactions were used to synthesize these derivatives. The reaction was carried out at room temperature by stirring in presence of ceric ammonium nitrate (CAN) as a green catalyst. The structures of the synthesized compounds were established by spectral studies. The synthesized derivatives 4(a–n) were evaluated for their in vitro anticancer activity against six human cancer cell lines by the SRB assay method. The cancer cell lines used in this research work are SK-MEL-2 (melanoma), MCF-7 (breast cancer), IMR-32 (neuroblastoma) MG-63 (human osteosarcoma), HT-29 (human colon cancer) and Hep-G2 (human hepatoma). All the synthesized derivatives inhibited the cell proliferation. Importantly, all the target compounds showed no cytotoxicity towards normal tissue cells (GI50 > 250 µM). A docking study was performed to predict the mode of action. Docking results indicate that the compounds have good binding with the enzyme tyrosine kinase as well as with microtubules, which makes them dual inhibitors. The result of in-silico bioavailability studies suggests that the compounds from the present series have good oral drug-like properties and are non-toxic in nature. In vivo acute oral toxicity study results indicate that the compounds can be considered safe, and therefore could be developed in the future as good anticancer agents or as leads for the design and synthesis of novel anticancer agents.

New Borane-Protected Derivatives of α-Aminophosphonous Acid as Anti-Osteosarcoma Agents: ADME Analysis and Molecular Modeling, In Vitro Studies on Anti-Cancer Activities, and NEP Inhibition as a Possible Mechanism of Anti-Proliferative Activity

“…Tumor cells are characterized by, e.g., an unlimited potential for proliferation [ 26 ]; hence, restriction of tumor cell proliferation via cell cycle arrest and/or apoptosis induction is an expected feature of new compounds with anti-cancer potential. It is reported that OP compounds, including those based on α-aminophosphonate scaffolds, exhibit anti-proliferative activity towards various types of cancer, e.g., leukemia, melanoma, colon cancer, hepatoma, breast cancer, lung cancer, and neuroblastoma [ 3 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. According to these reports, the growth inhibitory effect of αAPs was associated with apoptosis induction and cell cycle arrest mostly at the G 2 phase.…”

Recent advances in isatin hybrids as potential anticancer agents

“…Besides the isatin hybrids mentioned above, some other hybrids also showed certain anticancer activity, such as hybrid 61a (GI 50 : 0.75–28.39 μM, SRB assay) displayed broad‐spectrum activity against a panel of cancer cell lines derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers. [ 122–128 ] However, the majority of them were not superior to the references and still need to be modified.…”

Enantioselective synthesis of α-aryl α-hydrazino phosphonates

“… 9 Additionally, non-proteogenic α-hydrazino phosphonic acid derivatives, in which intramolecular H-bonds (hydrazino turns) 10 might modify their biological activities, have emerged as promising targets in medicinal chemistry. In particular, α-hydrazinophosphonate oxadiazoles I, 11 isatin derivatives II 12 and hydrazide III 4 a have been reported to exhibit promising activities against different types of cancer (I and II) and antimicrobial activity against K. Pneumonia (III) ( Fig. 1 ).…”