1. Chimerically designed HDAC- and tyrosine kinase inhibitors. A series of erlotinib hybrids as dual-selective inhibitors of EGFR, HER2 and histone deacetylases
Thomas Beckers, Siavosh Mahboobi,* Mathias Schmidt*. Med. Chem. Commun., 2012, 3, 829–835
Linking the erlotinib substructure with an N-(2-aminophenyl)-3-(1-sulfonyl-1H-pyrrol-3-yl)acrylamide results in inhibition of nuclear extract HDAC and HDAC 1 in the micromolar range (compound 10). The potency of the phenylenediamine inhibitors depends on the nature of the central linking system between the phenylenediamine and the erlotinib scaffold. In this series of HDAC inhibitors the compounds harboring an oxymethyl-benzamide (9a, 9b) or a sulfonylpyrrol-acrylamide (10) show an IC50 of inhibition of rHDAC 1 below 100 nM. This methylene-benzamide motif is also found in two benzamides in advanced clinical development named entinostat (4) and mocetinostat (5) (Fig. 1). The same magnitude of potency is seen in the sulfonylpyrrol-acrylamide (10). Changing the phenylenediamine structure motif to a hydroxamic acid leads to compound 11 with an inhibition of nuclear extract HDAC and HDAC 1 in the low nanomolar range. The IC50 values show approximately 10 times higher potency towards nuclear extract HDAC and rHDAC 1 than the reference compound SAHA.
2. Discovery of 3,3a,4,5-tetrahydro-2 -benzo[g ] indazole containing quinoxaline derivatives as novel EGFR/HER-2 dual inhibitors
Xi Zong, Jin Cai, Junqing Chen, Chunlong Sun, Lushen Li and Min Ji*. RSC Adv.,2015, 5,24814–24823
In this work, a series of pyrazole–quinoxaline derivatives that potentially function as inhibitors of EGFR and HER-2 kinases have been synthesized, and most of them exhibited potent aﬃnity for EGFR or HER-2 kinase as well as excellent anti-proliferative activity. Compound 4l showed excellent EGFR/HER-2 inhibitory activities and better antiproliferative activity against A549 and MCF-7 cell lines than Erlotinib. After analysis of the binding models of compounds 4l and 4x with EGFR, it was found that the models of compounds 4l or 4x in complex with the ATP binding site were similar to that of Erlotinib. The quinoxaline moiety might play a crucial role in the compounds’ EGFR inhibition activity by forming π-πinteractions and hydrogen bonding interactions with the residues in the binding pocket. Finally, QSAR models were built with the activity data and binding conformations to begin our work in this paper, as well as to provide a reliable tool for the reasonable design and synthesis of potent tyrosine kinase inhibitors. In conclusion, the preliminary evaluation results demonstrated that the newly developed tricyclic heterocycle-containing pyrazoles combined with a thiazolo quinoxaline ring, acting as potent dual EGFR and HER-2 inhibitors, may possess therapeutic potential for cancer treatment.
3. Fabrication of PVCL-co-PMMA nanoﬁbers with tunable volume phase transition temperatures and maintainable shape for anti-cancer drug release
Zaiqian Yu, Hongjuan Gu, Dongyan Tang*. RSC Adv.,2015, 5, 64944–64950
As to Erlotinib wrapped PVCL electrospinning materials, nanofibers swelled at temperature that below LCST and deswelled that above it. The sizes of the pores on the electrospinning mats would shrink and expand accordingly. Erlotinib particles could be of acid soluble and of slow dissolution behavior at neutral pH values. Thus the drug particles would penetrate the pores when the nanofibers were in shrinking state, and while would be trapped when the nanofibers were in expanding state. As reflected by Fig. 10(C) and (D), drug released at a faster rate at temperature that above the LCST values than that below one, indicating the positive relation of releases to temperatures. And although the drug particles were in trapped state at the “oﬀ” status, the nanofibers were still in more hydrophilic state while below the LCST values, and thus the gels were penetratable for drug molecules, so the drug still could be released.
4. A novel strategy for targeting photodynamic therapy Molecular combo of photodynamic agent zinc(II) phthalocyanine and small molecule target-based anticancer drug erlotinib
Feng-Ling Zhang, Qi Huang, Ke Zheng, Jun Li, Jian-Yong Liu* and Jin-Ping Xue*. Chem. Commun., 2013, 49, 9570—9572
In summary, we have synthesised and characterised two zinc(II) phthalocyanine–erlotinib conjugates and evaluated their in vitro photodynamic activities and selective affinity toward HepG2 cancer cells and A431 tumour tissues. The conjugates contain both photodynamic and targeting anti-cancer therapy agents which are covalently linked and function in a cooperative manner. The introduction of the erlotinib moiety can enhance the specificity of phthalocyanine units to HepG2 cancer cells and A431 tumour tissues. The IC50 value of the conjugates is as low as 0.01 mM toward the HepG2 cells, which is equivalent to that of the reference compound 4 without the erlotinib derivative. The tumour/skin ratio of the conjugate is actually about 5-fold higher than that of reference 4. The overall results show that the conjugates are highly promising antitumour agents for dual targeting and photodynamic therapy. This may provide a novel targeting strategy for PDT, as well as other cancer therapy modalities.