Manlio Palumbo

Università degli Studi di Padova, Department of Pharmaceutical and Pharmacological Sciences, Faculty Member

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Papers by Manlio Palumbo

Of magic bullets, multiple targets, and artificial intelligence. Are we all set to defeat cancer?

Arkivoc

Personalized medicine applied to patients with complex diseases, like cancer, grants a better qua... more Personalized medicine applied to patients with complex diseases, like cancer, grants a better quality of life and longer survival. However, in most instances it is not curative, due to the onset of two main obstacles represented by undesired toxicity and/or drug resistance, which contribute to a different extent depending upon the inhibition mechanism. In this short commentary, we try to combine the idea of multi-targeting agents with an Artificial Intelligence platform to further improve patients' treatment and allowing them to be cured or live essentially disease-free.

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Chromophore-Modified Antitumor Anthracenediones: Synthesis, DNA Binding, and Cytotoxic Activity of 1,4-Bis[(aminoalkyl)amino]benzo[g]phthalazine-5,10-diones

Journal of Medicinal Chemistry, 1995

As part of a program aimed at exploring the effect of the introduction of heteroatoms into the an... more As part of a program aimed at exploring the effect of the introduction of heteroatoms into the anthracene-9,10-dione chromophore, we have synthesized novel 1,4-bis[(aminoalkyl)amino]-benzo[g]phthalazine-5,10-diones (BPDs) 1 which are related to the antitumor agents ametantrone and mitoxantrone. Derivatives 1 were prepared by chromic acid oxidation of acylated benzo[g]phthalazines 5 followed by acid hydrolysis or by silylation-amination of 5,10-dihydroxybenzo[g]phthalazine-1,4-dione (8). The 1-[(aminoalkyl)amino]-4-amino congeners 2 were isolated in low yields as byproducts from the oxidation of 5. Against a panel of human tumor cell lines, the benzo[g]phthalazine-5,10-diones 1 and 2 exhibited cytotoxic activity comparable or even superior to that of mitoxantrone. In compounds 1, structure-activity relationships different than those operative in the carbocyclic series appeared to emerge. DNA-binding studies with the ametantrone-like compound 1c and its single-armed congener 2c indicated that the introduction of a 2,3-diaza subunit into the anthracene-9,10-dione chromophore reduces the affinity of the drug for DNA in comparison with ametantrone. On the other hand, the number of side-chain groups does not affect binding to a great extent. These findings seem to suggest mechanisms of cell death other than those induced by simple interaction of the 1,4-BPDs 1 and 2 with DNA.

Modeling and Biological Investigations of an Unusual Behavior of Novel Synthesized Acridine-Based Polyamine Ligands in the Binding of Double Helix and G-Quadruplex DNA

ChemMedChem, 2010

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Antitumor AZA-anthrapyrazoles: biophysical and biochemical studies on 8- and 9-aza regioisomers

Biochemical Pharmacology, 2004

Aza-bioisosteres of anthrapyrazoles (Aza-APs) bearing the C-N substitution at position 9 are powe... more Aza-bioisosteres of anthrapyrazoles (Aza-APs) bearing the C-N substitution at position 9 are powerful anticancer agents now in clinical trials. In contrast, their 8-substituted regioisomers are practically devoid of chemotherapeutic effects. To understand the molecular basis for a dramatically different response by otherwise very similar compounds, we performed a detailed investigation on the physico-chemical properties of several aza-APs belonging to the two families, on their DNA-binding affinity and specificity as well as on their capacity to impair the activity of the two isoforms of human Topoisomerase II (top2a and top2b). Our results indicate that molecular size and shape, electronic distribution, redox properties, lipophilicity and protonation equilibria are essentially the same when comparing 9-with 8substituted congeners. Although no major difference could be picked up when comparing the DNA binding properties of corresponding members of the 8-and 9-aza families, interestingly the affinity and specificity for the nucleic acid is modulated by the nature of the sidearms linked to the aza-AP scaffold, suggesting structural motifs that may determine DNA sequence recognition by the studied drug. Topoisomerase II poisoning activity was much higher for 9-aza derivatives than 8-aza analogues as shown by a cleavage assay with purified recombinant top2 isoforms. The difference appears to account for the divergent anticancer potential exhibited by different aza-AP regioisomers and suggests a specific molecular recognition of the cleavage complex by the studied drugs.

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Mapping Simocyclinone D8 Interaction with DNA Gyrase: Evidence for a New Binding Site on GyrB

Antimicrobial Agents and Chemotherapy, 2009

Simocyclinone D8, a coumarin derivative isolated from Streptomyces antibioticus Tü 6040, represe... more Simocyclinone D8, a coumarin derivative isolated from Streptomyces antibioticus Tü 6040, represents an interesting new antiproliferative agent. It was originally suggested that this drug recognizes the GyrA subunit and interferes with the gyrase catalytic cycle by preventing its binding to DNA. To further characterize the mode of action of this antibiotic, we investigated its binding to the reconstituted DNA gyrase (A 2 B 2 ) as well as to its GyrA and GyrB subunits and the individual domains of these proteins, by performing protein melting and proteolytic digestion studies as well as inhibition assays. Two binding sites were identified, one (anticipated) in the N-terminal domain of GyrA (GyrA59) and the other (unexpected) at the C-terminal domain of GyrB (GyrB47). Stabilization of the A subunit appears to be considerably more effective than stabilization of the B subunit. Our data suggest that these two distinct sites could cooperate in the reconstituted enzyme.

Peptidyl Anthraquinones as Potential Antineoplastic Drugs: Synthesis, DNA Binding, Redox Cycling, and Biological Activity

Journal of Medicinal Chemistry, 1996

A series of new compounds containing a 9,10-anthracenedione moiety and one or two peptide chains ... more A series of new compounds containing a 9,10-anthracenedione moiety and one or two peptide chains at position 1 and/or 4 have been synthesized. The amino acid residues introduced are glycine (Gly), lysine (Lys), and tryptophan (Trp), the latter two in both the Land Dconfigurations. The peptidyl anthraquinones maintain the ability of intercalating efficiently into DNA, even though the orientation within the base-pair pocket may change somewhat with reference to the parent drugs mitoxantrone (MX) and ametantrone (AM). The interaction constants of the mono-, di-, and triglycyl derivatives are well comparable to those found for AM but 5-10 times lower than the value reported for MX. On the other hand, the glycyl-lysyl compounds bind DNA to the same extent as (L-isomer) or even better than (D-isomer) MX. As for the parent drugs without peptidyl chains, the new compounds prefer alternating CG binding sites, although to different extents. The bis-Gly-Lys derivatives are the least sensitive to base composition, which may be due to extensive aspecific charged interactions with the polynucleotide backbone. As far as redox properties are concerned, all peptidyl anthraquinones show a reduction potential very close to that of AM and 60-80 mV less negative than that of MX; hence, they can produce free-radical-damaging species to an extent similar to the parent drugs. The biological activity has been tested in human tumor and murine leukemia cell lines. Most of the test anthraquinones exhibit cytotoxic properties close to those of AM and considerably lower than those of MX. Stimulation of topoisomerase-mediated DNA cleavage is moderately present in representatives of the glycylanthraquinone family, whereas inhibition of the background cleavage occurs when Lys is present in the peptide chain. For most of the test anthraquinones, the toxicity data are in line with the DNA affinity scale and the topoisomerase II stimulation activity. However, in the lysyl derivatives, for which lack of cytotoxicity cannot be related to poor binding to DNA, the steric and electronic properties of the side-chain substituent must impair an effective recognition of the cleavable complex.

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Discovery of wt RET and V804M RET Inhibitors: From Hit to Lead

ChemMedChem

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Virtual Cross-Linking of the Active Nemorubicin Metabolite PNU-159682 to Double-Stranded DNA

Chemical research in toxicology, Jan 20, 2017

The DNA alkylating mechanism of PNU-159682 (PNU), a highly potent metabolite of the anthracycline... more The DNA alkylating mechanism of PNU-159682 (PNU), a highly potent metabolite of the anthracycline nemorubicin, was investigated by gel-electrophoretic, HPLC-UV, and micro-HPLC/mass spectrometry (MS) measurements. PNU quickly reacted with double-stranded oligonucleotides, but not with single-stranded sequences, to form covalent adducts which were detectable by denaturing polyacrylamide gel electrophoresis (DPAGE). Ion-pair reverse-phase HPLC-UV analysis on CG rich duplex sequences having a 5'-CCCGGG-3' central core showed the formation of two types of adducts with PNU, which were stable and could be characterized by micro-HPLC/MS. The first type contained one alkylated species (and possibly one reversibly bound species), and the second contained two alkylated species per duplex DNA. The covalent adducts were found to produce effective bridging of DNA complementary strands through the formation of virtual cross-links reminiscent of those produced by classical anthracyclines in...

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G-quadruplexes in human promoters: a challenge for therapeutic applications

Biochimica et biophysica acta, Jan 23, 2016

G-rich sequences undergo unique structural equilibria to form G-quadruplexes (G4) both in vitro a... more G-rich sequences undergo unique structural equilibria to form G-quadruplexes (G4) both in vitro and in cell systems. Several pathologies emerged to be directly related to G4 occurrence at defined genomic portions. Additionally, G-rich sequences are significantly represented around transcription start sites (TSS) thus leading to the hypothesis of a gene regulatory function for G4. Thus, the tuning of G4 formation has been proposed as a new powerful tool to regulate gene expression to treat related pathologies. However, up-to date this approach did not provide any new really efficient treatment. Here, we summarize the most recent advances on the correlation between the structural features of G4 in human promoters and the role these systems physiologically exert. In particular we focus on the effect of G4 localization among cell compartments and along the promoters in correlation with protein interaction networks and epigenetic state. Finally the intrinsic structural features of G4 at ...

Molecular Basis for Differential Recognition of G-Quadruplex versus Double-Helix DNA by Bis-Phenanthroline Metal Complexes

ChemMedChem, 2016

1,10-Phenanthroline (Phen) derivatives are attractive ligands to provide metal complexes that are... more 1,10-Phenanthroline (Phen) derivatives are attractive ligands to provide metal complexes that are selective for different DNA secondary structures. Herein, we analyze the binding processes of two bis-Phen analogues and their Ni(II) complexes toward double-stranded DNA and telomeric G-quadruplex DNA by calorimetric and spectroscopic techniques. The free ligands can adapt to both DNA arrangements. Conversely, metal ion coordination produces an increase in ligand affinity for the tetrahelical structure, whereas it dramatically decreases binding to double-stranded DNA as a result of distinct binding modes on the two templates. In fact, Ni(II) complexes effectively stack on the G-quadruplex terminals, with an entropic loss counterbalanced by favorable enthalpy changes, whereas they cause a conformational reshaping of the double-helix form with a substantial decrease in the binding free energy. Consistently, no Ni(II) -DNA ionic pair has ever been identified. These results provide a rationale for the selective recognition of distinct DNA arrangements in view of targeted pharmacological applications.

2,6-Di(ω-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5- mn ]pyrimido[5,6,1- de ]acridine-5,7-diones: Novel, Potent, Cytotoxic, and DNA-Binding Agents

J Med Chem, 2002

... Ippolito Antonini,* Paolo Polucci, Amelia Magnano, Barbara Gatto, § Manlio Palumbo, §... more

On the Oxy Analogues to the 4 --> 1 Intramolecularly Hydrogen-Bonded Peptide Conformations

Macromolecules, 1976

ChemInform Abstract: Tricyclic Indenopyridazine Derivatives: Synthesis, Cytotoxic Activity and DNA-Binding Properties

Cheminform, 2010

Tricyclic Indenopyridazine Derivatives: Synthesis, Cytotoxic Activity and DNA-Binding Properties.... more Tricyclic Indenopyridazine Derivatives: Synthesis, Cytotoxic Activity and DNA-Binding Properties.-The indenopyridazones (I)-(III) are submitted to a series of modifications with the aim to obtain a new class of intercalating agents. The new compounds are tested for their cytotoxic activity on human colon carcinoma cell lines and murine leukemia cell lines in comparison with cisplatin, melphalan, and doxorubicin. DNA-binding studies are carried out to verify intercalating properties. A double bound in 4,4a-position seems to be essential for activity and derivates of (II) are more potent than the corresponding derivatives of (III). Compounds (V) and (VIII) compare favorably with cisplatin and melphalan, against resistant and both sensitive and resistant cell lines, respectively.

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Reazioni di riduzioni stereospcifica mediante l'uso di catalizzatori Palladio-poli-alfa-amminoacidi

Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models

Oncotarget, 2016

Stabilization of G-quadruplex (G4) structures in promoters is a novel promising strategy to regul... more Stabilization of G-quadruplex (G4) structures in promoters is a novel promising strategy to regulate gene expression at transcriptional and translational levels. c-KIT proto-oncogene encodes for a tyrosine kinase receptor. It is involved in several physiological processes, but it is also dysregulated in many diseases, including cancer. Two G-rich sequences able to fold into G4, have been identified in c-KIT proximal promoter, thus representing suitable targets for anticancer intervention. Herein, we screened an "in house" library of compounds for the recognition of these G4 elements and we identified three promising ligands. Their G4-binding properties were analyzed and related to their antiproliferative, transcriptional and post-transcriptional effects in MCF7 and HGC27 cell lines. Besides c-KIT, the transcriptional analysis covered a panel of oncogenes known to possess G4 in their promoters.From these studies, an anthraquinone derivative (AQ1) was found to efficiently do...

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Regioisomeric bis6(aminoalkyl)amino9 aza-anthracenedione derivatives: Effects of the side chain position upon DNA binding and biological activity

Eur J Pharm Sci, 1998

DNA-based aptamers for human cathepsin G

A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line

Cancer Research, Aug 15, 2001

We selected a mitoxantrone-resistant HT29 colon carcinoma cell line (HT29/MIT) that exhibited a v... more We selected a mitoxantrone-resistant HT29 colon carcinoma cell line (HT29/MIT) that exhibited a very high degree of resistance to the selecting agent and marked resistance to topotecan and SN38, but limited resistance to doxorubicin. The development of drug resistance was independent of expression of P-glycoprotein or multidrug resistance-associated protein but was associated with high up-regulation of the breast carcinoma resistance protein (BCRP) as shown by Western blot analysis. BCRP overexpression was associated with a reduced intracellular accumulation of topotecan, a known substrate for BCRP. Conversely, a lipophilic 7modified camptothecin analogue (ST1481) displayed a complete lack of cross-resistance in HT29/MIT cells, suggesting that the drug was not a substrate for BCRP because no defects in intracellular accumulation were found. This conclusion is consistent with the antitumor efficacy of ST1481 against a BCRP-expressing tumor. These results may have therapeutic implications because the antitumor efficacy of ST1481 is in part related to a good bioavailability after oral administration, and the drug is currently under Phase I clinical evaluation.

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ChemInform Abstract: 6-Hydroxy Derivative as New Desfluoroquinolone (DFQ): Synthesis and DNA-Binding Study

Cheminform, 2010

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Inhibition of Human Immunodeficiency Virus Type 1 Tat-trans-Activation-Responsive Region Interaction by an Antiviral Quinolone Derivative

Antimicrobial Agents and Chemotherapy, May 1, 2004

ABSTRACT WM5, a 6-aminoquinolone derivative, binds with high affinity to the bulge of the trans-a... more ABSTRACT WM5, a 6-aminoquinolone derivative, binds with high affinity to the bulge of the trans-activation-responsive region (TAR), whereas it displays low binding affinity for the loop and stem regions of TAR and for random RNA and DNA sequences. Furthermore, WM5 disrupts the natural protein-nucleic acid complex with a 50% inhibitory concentration in the low micromolar range in both in vitro and in vivo assays.

Manlio Palumbo

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