Development of multifunctional anticancer agents: design, synthesis and evaluation of hybrid compounds containing kinase inhibitor moieties

Cancer is a complex and a multiple-genes involved disease; for this reason it can not be treated or cured with a single drug modulating the biological function of a single target. The innovation related to multi-targeted drugs, combining the activity of different cancer progression relevant targets, became a burgeoning research topic. Drugs that act on multiple targets can enhance efficacy and reduce chemo-resistance that causes disease relapse and metastasis and remains the main obstacle to cancer therapy. One of the main target nowadays are tyrosine kinases (TKs); since most protein kinases stimulate cell growth and proliferation, cell survival and migration, they can, if overexpressed, amplified or constitutively active, assume oncogenic properties. Other ideal biological targets are enzymes as histone deacetylases (HDAC) and mitochondrial functions. Herein we present the development and the preliminary evaluation of new Abl/HDAC inhibitors bearing the pyrido-pyrimidine main scaffold; the functionalization of the most active compounds with metal ions (i.e. Zn2+, Cu2+ and Fe3+); the development of novel multi-kinase inhibitors bearing the 4-anilinopyrimidine scaffold; the development of novel cKIT/wtRET/V804MRET inhibitors bearing the 4-anilinopyridine scaffold. Besides, the development of multi-kinase inhibitors endowed with antifibrotic properties as well as novel topoisomerase inhibitors are reported

Targeting kinases with anilinopyrimidines: Discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily

Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multityrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N\u2019-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds

Synthesis and reactivity of cytotoxic platinum(II) complexes of bidentate oximes: a step towards the functionalization of bioactive complexes

Two new platinum(II) complexes bearing triphenylphosphine and bidentate oxime ligands [Pt(Cl)(PPh3){(κ2-N,O)-(1{C(R)=N(OH)-2(O)C10H6})}] (R = H, Me) were synthesized in good yields from trans-[PtCl(μ-Cl)(PPh3)]2. The structure of [Pt(Cl)(PPh3){(κ2-N,O)-(1{CH=N(OH)-2(O)C10H6})}] was determined by single-crystal X-ray diffraction. Both complexes showed good antiproliferative properties in vitro against HeLa, A2780, and A2780cis cancer cell lines. They reacted cleanly with alkylating agents in the presence of aqueous bases under phase-transfer catalysis conditions to afford the corresponding O-alkylation products [Pt(Cl)(PPh3){(κ2-N,O)-(1{HC=N(OR′)-2(O)C10H6})}] [R′ = CH2CH2Cl, CH2Ph, (CH2)4Br] in good yields

Development of multifunctional anticancer agents: design, synthesis and evaluation of hybrid compounds containing kinase inhibitor moieties

Cancer is a complex and a multiple-genes involved disease; for this reason it can not be treated or cured with a single drug modulating the biological function of a single target. The innovation related to multi-targeted drugs, combining the activity of different cancer progression relevant targets, became a burgeoning research topic. Drugs that act on multiple targets can enhance efficacy and reduce chemo-resistance that causes disease relapse and metastasis and remains the main obstacle to cancer therapy. One of the main target nowadays are tyrosine kinases (TKs); since most protein kinases stimulate cell growth and proliferation, cell survival and migration, they can, if overexpressed, amplified or constitutively active, assume oncogenic properties. Other ideal biological targets are enzymes as histone deacetylases (HDAC) and mitochondrial functions. Herein we present the development and the preliminary evaluation of new Abl/HDAC inhibitors bearing the pyrido-pyrimidine main scaffold; the functionalization of the most active compounds with metal ions (i.e. Zn2+, Cu2+ and Fe3+); the development of novel multi-kinase inhibitors bearing the 4-anilinopyrimidine scaffold; the development of novel cKIT/wtRET/V804MRET inhibitors bearing the 4-anilinopyridine scaffold. Besides, the development of multi-kinase inhibitors endowed with antifibrotic properties as well as novel topoisomerase inhibitors are reported.Il cancro è una patologia complessa che coinvolge più geni; per questo motivo non può essere trattato o curato con un singolo farmaco che regola l'attività biologica di un unico bersaglio. L'innovazione dei farmaci multi-target, che combinano l'attività contro diversi bersagli coinvolti nella progressione del tumore, è diventato un promettente argomento di ricerca. Farmaci che agiscono su più bersagli possono aumentare l'efficacia della terapia riducendo il fenomeno di resistenza che causa ricadute e metastasi restando uno dei maggiori ostacoli della terapia antitumorale. Le tirosin-chinasi sono considerate ad oggi tra i principali bersagli in quanto molte protein chinasi stimolando la crescita, la proliferazione e la migrazione cellulare e se sovra espresse, amplificate o costitutivamente attivate assumono proprietà oncogeniche. Altri bersagli biologici ideali sono enzimi quali gli istone deacetilasi e le funzioni mitocondriali. Nella tesi sono presentati lo sviluppo e la valutazione biologica preliminare di nuovi inibitori duali di Abl e HDAC caratterizzati da una porzione pirido-pirimidinica; la funzionalizzazione dei composti più attivi con ioni metallici (i.e. Zn2+, Cu2+ and Fe3+); lo sviluppo di nuovi inibitori multi-chinasi caratterizzati da una porzione 4-anilinopirimidinica; lo sviluppo di nuovi inibitori di cKIT/wtRET/V804MRET a struttura 4-anilinopiridinica. Sono inoltre riportati lo sviluppo di nuovi inibitori multichinasici ad attività antifibrotica ed inibitori di topoisomerasi

Novel benzoquinoline derivatives via unpredicted condensation of ethyl propiolate and naphthylamines: Synthesis and topoisomerase inhibition activity

An unpredicted condensation of naphthylamine with two molecules of ethyl propiolate yields directly carbethoxy benzoquinoline in high yield. Some benzoquinoline carboxamide derivatives with protonatable side chains were then synthesized and evaluated for antiproliferative activity on human tumor cell lines. The most active compound (7a) demonstrated to intercalate into DNA and to inhibit the relaxation activity mediated by topoisomerase II

Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N\u2019-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of Type III receptor tyrosine kinase subfamily

Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi-target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis the kinase profiling and the biological evaluation of a set of novel 4-anilinopyrimidines as promising anticancer compounds. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds. Among synthesized compounds, N-phenyl-N\u2019-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives targeted some members of type III receptor tyrosine kinase family. In particular, compound 24 was identified as a selective dual KIT/PDGFRbeta inhibitor. The compound was more cytotoxic than sunitinib against A549 and PxPC3 human cancer cell lines, and showed a preferential antiproliferative activity toward neoplastic rather than HEK293 non-tumor cells. Overall, our data suggested that the 4-anilino-6-phenylpyrimidines constitute a promising class of subfamily selective inhibitors of Type III RTKs subfamily. These results are of remarkably importance since, despite the huge interest in identifying subfamily selective kinase inhibitors, poorly toxic and highly active as antitumor agents, nowadays there is still a paucity of reports investigating their antitumor activity

Metal-Tyrosine Kinase Inhibitors: Targeted Metal-drug Conjugates

Tyrosine Kinases are enzymes that catalyse the phosphorylation of the tyrosine residues of their substrates and activate downstream pathways involved in cellular proliferation. Their overexpression/hyper-activity is implicated in numerous different cancerous cell lines. Small molecule Tyrosine Kinase Inhibitors (TKi’s), such as Imatinib, Erlotinib and Sunitinib have been developed as targeted anti-cancer chemotherapeutics but, at the moment, their clinical usage is hindered due to acquired and innate resistance and/or dose limiting side effects. Recently, Metal-Tyrosine Kinase Inhibitor conjugates have become a promising field to overtake these drawbacks since the TKi’s show potential to improve selectivity and pharmacological properties of metal-based drugs, overcoming the resistance associated with current TKi’s. Metal-Tyrosine Kinase Inhibitor conjugates further find applications is several biological fields as dual-modal activity drugs, pro-drug systems and selective metal theragnostics. In this review, advancements over the past decade in the field of metal based-TKi conjugates are discussed and insights are provided to successfully develop metal – TKi conjugates. Three main TK targets are discussed, EGFR (Epidermal Growth Factor Receptor), PDGFR (Platelet Derived Growth Factor Receptor) VEGFR (Vascular Endothelial Growth Factor Receptor). Future perspectives and applications of this promising research area are also outlined

Metal-Tyrosine Kinase Inhibitors: Targeted Metal-drug Conjugates

Tyrosine Kinases are enzymes that catalyse the phosphorylation of the tyrosine residues of their substrates and activate downstream pathways involved in cellular proliferation. Their overexpression/hyper-activity is implicated in numerous different cancerous cell lines. Small molecule Tyrosine Kinase Inhibitors (TKi’s), such as Imatinib, Erlotinib and Sunitinib have been developed as targeted anti-cancer chemotherapeutics but, at the moment, their clinical usage is hindered due to acquired and innate resistance and/or dose limiting side effects. Recently, Metal-Tyrosine Kinase Inhibitor conjugates have become a promising field to overtake these drawbacks since the TKi’s show potential to improve selectivity and pharmacological properties of metal-based drugs, overcoming the resistance associated with current TKi’s. Metal-Tyrosine Kinase Inhibitor conjugates further find applications is several biological fields as dual-modal activity drugs, pro-drug systems and selective metal theragnostics. In this review, advancements over the past decade in the field of metal based-TKi conjugates are discussed and insights are provided to successfully develop metal – TKi conjugates. Three main TK targets are discussed, EGFR (Epidermal Growth Factor Receptor), PDGFR (Platelet Derived Growth Factor Receptor) VEGFR (Vascular Endothelial Growth Factor Receptor). Future perspectives and applications of this promising research area are also outlined

Metal-Tyrosine Kinase Inhibitors: Targeted Metal-drug Conjugates

Tyrosine Kinases are enzymes that catalyse the phosphorylation of the tyrosine residues of their substrates and activate downstream pathways involved in cellular proliferation. Their overexpression/hyper-activity is implicated in numerous different cancerous cell lines. Small molecule Tyrosine Kinase Inhibitors (TKi’s), such as Imatinib, Erlotinib and Sunitinib have been developed as targeted anti-cancer chemotherapeutics but, at the moment, their clinical usage is hindered due to acquired and innate resistance and/or dose limiting side effects. Recently, Metal-Tyrosine Kinase Inhibitor conjugates have become a promising field to overtake these drawbacks since the TKi’s show potential to improve selectivity and pharmacological properties of metal-based drugs, overcoming the resistance associated with current TKi’s. Metal-Tyrosine Kinase Inhibitor conjugates further find applications is several biological fields as dual-modal activity drugs, pro-drug systems and selective metal theragnostics. In this review, advancements over the past decade in the field of metal based-TKi conjugates are discussed and insights are provided to successfully develop metal – TKi conjugates. Three main TK targets are discussed, EGFR (Epidermal Growth Factor Receptor), PDGFR (Platelet Derived Growth Factor Receptor) VEGFR (Vascular Endothelial Growth Factor Receptor). Future perspectives and applications of this promising research area are also outlined

Biphenylaminoquinazolines as novel dual inhibitors of tyrosine kinases and tubulin polymerization: synthesis, SARs and anticancer properties

The discovery of the anticancer drugs erlotinib and gefitinib in the early 2000\u2019s prompted intensive research on 4-anilinoquinazoline compounds. The main biomolecular target for this class of compounds remains the Epidermal Growth Factor Receptor (EGFR), although some compounds do not show high selectivity for it. Cell cycle experiments with our previously reported 4-biphenylaminoquinazolines multi-tyrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. While previous compounds acted as dual inhibitors, the new heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. On the contrary, the absence of a dioxygenated fused ring led to compounds inactive against tubulin polymerization. The most interesting compounds were cytotoxic in both OVCAR-8 (human ovarian carcinoma) and NCI/ADR-RES (human ovarian carcinoma P-glycoprotein overexpressing) cell lines at nanomolar concentration