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1.
Anticancer Agents Med Chem ; 19(10): 1276-1284, 2019.
Article in English | MEDLINE | ID: mdl-30848212

ABSTRACT

BACKGROUND: The 1,8-Naphthalimides constitute an important class of biologically active, DNAbinding compounds. There are no available data on the synthesis of 1,8-naphthalimide derivatives with nonprotein amino acids and their biological activity. The aim of this paper was to determine the synthesis, structural characterization and cytotoxic activity of new 1-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)cycloalkane-1- carboxylic acids with 5-, 6-, 7-, 8- and 12-membered rings as well as 2-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)- yl)adamantane-2-carboxylic acid and 1-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-1,2,3,4-tetrahydronaphthalene- 1-carboxylic acid. METHODS: The target compounds were obtained by an interaction of 1,8-naphthalic anhydride with a series of non-protein amino acids. The optimized geometry and harmonic vibrational frequencies have been calculated by DFT employing B3LYP functional using 6-31G(d,p) basis set. An ab initio (MP2 and Hartee-Fock) and DFT (different functionals) using several basis sets have been applied for NMR calculations. The cytotoxic effects of the synthesized compounds are assessed against two human tumor cell lines, namely K-562 (chronic myeloid leukemia) and HUT-78 (cutaneous T-cell lymphoma) after 72 h exposure, using the MTT-dye reduction assay. The apoptogenic effects and the ability to modulate the NFκB-signaling pathways were determined using commercially available ELISA kits. RESULTS: All compounds inhibited the growth of malignant cells at micromolar concentrations whereby compound 4b (1-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)cyclohexane-1-carboxylic acid) demonstrated superior activity in both cell lines with IC50 values comparable to those of the reference anticancer drug melphalan. CONCLUSION: New 1,8-naphthalimide derivatives with non-protein amino acids were successfully synthesized. Quantum-chemical calculations were performed to elucidate the structure of the newly synthesized compounds. There is a proper alignment between theoretical and experimental results. The cytotoxicity of the synthesized products against two human tumor cell lines, namely K-562 and HUT-78 was evaluated. All compounds inhibited the growth of malignant cells at micromolar concentrations. The pharmacodynamics evaluation of compound 4b showed that its cytotoxicity is mediated by induction of apoptosis and inhibition of NFκB-signaling.


Subject(s)
Amino Acids/chemistry , Antineoplastic Agents/chemical synthesis , Naphthalimides/chemical synthesis , Naphthalimides/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Density Functional Theory , Humans , Models, Molecular , Molecular Structure
2.
Amino Acids ; 47(5): 1007-13, 2015 May.
Article in English | MEDLINE | ID: mdl-25655387

ABSTRACT

Some modified octapeptide analogs of somatostatin with the following structure D-Phe-c(Cys-Phe-D-Trp-Xxx-Yyy-Cys)-Thr-NH2, where Xxx is Lys or Orn and Yyy is Aib (α-aminoisobutyric acid), Ac5c (1-aminocyclopentanecarboxylic acid) or Ac6c (1-aminocyclohexane carboxylic acid) have been synthesized. The peptides were prepared by standard Fmoc-solid phase peptide chemistry method. The direct disulphide bond formation has been employed on the solid phase by Tl(CF3CO2)3. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29 (human colorectal cancer cell line), MDA-MB-23 (human breast cancer cell line), Hep-G2 (human hepatocellular carcinoma cell line), HeLa (cervical cancer cell line) and normal human diploid cell line Lep-3. The new peptides exhibited different concentration-dependent antiproliferative effect against the tumor cell lines after 24 h treatment. The compounds were most effective to the HT-29 tumor cells. The compound 4C (Orn(5), Aib(6)) demonstrated the most pronounced antiproliferative effects on HT-29 cells with the IC50 = 0.0199 µM.


Subject(s)
Antineoplastic Agents/chemical synthesis , Biomimetic Materials/chemical synthesis , Oligopeptides/chemical synthesis , Somatostatin/chemistry , Amino Acid Sequence , Amino Acids, Cyclic/chemistry , Aminoisobutyric Acids/chemistry , Antineoplastic Agents/pharmacology , Biomimetic Materials/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cyclohexanecarboxylic Acids/chemistry , Cycloleucine/chemistry , Dose-Response Relationship, Drug , HT29 Cells , HeLa Cells , Humans , Molecular Sequence Data , Oligopeptides/pharmacology , Solid-Phase Synthesis Techniques , Structure-Activity Relationship
3.
Amino Acids ; 43(4): 1445-50, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22237947

ABSTRACT

The cytotoxic effects of novel racemic and optically active constrained N-phosphonoalkyl bicyclic ß-amino acids were tested against a panel of human tumor cell lines. All of the compounds investigated exhibited different concentration-dependent antiproliferative effects against the HT-29, MDA-MB-231, HepG2 and HeLa cell lines after 24 h treatment. The most sensitive cells were the HeLa cells at various concentrations of the four compounds tested. The aminophosphonate 3 exerted the most pronounced antiproliferative effect against the HeLa cells (inhibition of the cell vitality up to 70% at 0.5 mg/ml) and was not toxic to the normal Lep3 cells at lower concentration. Furthermore, the N-phosphonophenyl derivatives 1 and 2 displayed antiproliferative effect against mainly the MDA-MB-231 tumour cells at higher concentration.


Subject(s)
Amino Acids/pharmacology , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds/pharmacology , Organophosphonates/pharmacology , Amino Acids/chemical synthesis , Antineoplastic Agents/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Organophosphonates/chemical synthesis , Stereoisomerism
4.
Amino Acids ; 43(3): 1217-23, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22143428

ABSTRACT

New series of N-modified analogues of the N/OFQ(1-13)NH(2) with aminophosphonate moiety have been synthesized and investigated for biological activity. These peptides were prepared by solid-phase peptide synthesis-Fmoc-strategy. The N/OFQ(1-13)NH(2) analogues were tested for agonistic activity in vitro on electrically stimulated rat vas deferens smooth-muscle preparations isolated from Wistar albino rats. Our study has shown that the selectivity of the peptides containing 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids to the N-side of Phe is not changed-they remain selective agonists of NOP receptors. The derivative with the largest ring (NOC-6) demonstrated efficacy similar to that of N/OFQ(1-13)NH(2), but in a 10-fold higher concentration. The agonistic activity of newly synthesized N-modified analogues of N/OFQ(1-13)NH(2) with aminophosphonate moiety was investigated for the first time.


Subject(s)
Opioid Peptides/pharmacology , Organophosphonates/pharmacology , Peptide Fragments/pharmacology , Receptors, Opioid/agonists , Amino Acid Sequence , Animals , Electric Stimulation , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Opioid Peptides/chemical synthesis , Organophosphonates/chemical synthesis , Peptide Fragments/chemical synthesis , Rats , Rats, Wistar , Structure-Activity Relationship , Vas Deferens/drug effects , Vas Deferens/physiology , Nociceptin Receptor , Nociceptin
5.
Amino Acids ; 39(5): 1537-43, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20499257

ABSTRACT

The aim of the present study was the synthesis and the biological screening of new analogs of Ac-RYYRWK-NH2, modified at the N-terminal with 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids. The four newly synthesized ligands for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) have been prepared by solid-phase peptide synthesis--Fmoc-strategy. These compounds were tested for agonistic activity in vitro on electrically stimulated smooth-muscle preparations isolated from vas deferens of Wistar rats. Our data showed that substitution of Arg at position 1 with aminophosphonates moiety decreased significantly the affinity of ligands to the NOP receptor. Furthermore, the enlargement of the cycle (with 5-8 carbon atoms) additionally diminished both the activity and the selectivity for NOP-receptor.


Subject(s)
Muscle, Smooth/drug effects , Organophosphonates/chemistry , Peptides/chemical synthesis , Peptides/pharmacology , Receptors, Opioid/metabolism , Vas Deferens/drug effects , Animals , Electric Stimulation , Ligands , Male , Molecular Structure , Molecular Weight , Muscle, Smooth/physiology , Peptides/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Vas Deferens/physiology , Nociceptin Receptor
6.
Amino Acids ; 38(1): 23-30, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19229586

ABSTRACT

Aminophosphonic acids are an important group of medicinal compounds, and their synthesis has been a focus of considerable attention in synthetic organic chemistry as well as medicinal chemistry. Although the phosphonic and carboxylic acid groups differ considerably with respect to shape, size, and acidity, alpha-aminophosphonic acids are considered to be structural analogues of the corresponding amino acids and the transition state mimics peptide hydrolysis. This review summarizes recent developments in the synthesis, characterization and biological activity of alpha-aminophosphonic acid and N-analogues. An account of both uses will be presented, emphasizing one of the potential future developments, and some implications in medicinal chemistry are also disclosed. In addition, a brief account on the characterization of N-(phosphonomethyl) glycine derivatives will be presented.


Subject(s)
Chemistry, Pharmaceutical , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Animals , Humans , Molecular Structure , Organophosphonates/chemistry
7.
Eur J Med Chem ; 43(6): 1199-205, 2008 Jun.
Article in English | MEDLINE | ID: mdl-17950497

ABSTRACT

A series of Calpha,alpha-disubstituted cyclic derivatives of N-(phosphonomethyl) glycine have been synthesized and characterized. They exhibited moderate clastogenicity, low antiproliferative activity on mice bone marrow cells and well expressed cytotoxicity against human tumor cell lines. The 8- and 12-membered cyclic analogs proved superior to the remaining compounds and were found to trigger apoptotic cell death in DOHH-2 cells. The latter compound caused 50% inhibition of the viability of hemobastose-derived cell lines at concentrations ranging from 20 to 67 microM.


Subject(s)
Glycine/analogs & derivatives , Apoptosis/drug effects , Cell Line , Drug Design , Drug Screening Assays, Antitumor , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Magnetic Resonance Spectroscopy , Mutagens/pharmacology , Spectrophotometry, Infrared , Glyphosate
8.
Bioorg Med Chem Lett ; 16(15): 4071-4, 2006 Aug 01.
Article in English | MEDLINE | ID: mdl-16714110

ABSTRACT

The purpose of the present study was the synthesis and the biological screening of new analogues of N/OFQ(1-13)NH2, the minimal sequence maintaining the same activity as the natural peptide nociceptin. In order to investigate the role of Lys, we substituted Lys at positions 9 and/or 13 by Orn, Dab (diaminobutanoic acid) or Dap (diaminopropanoic acid). The new N/OFQ(1-13)NH2 analogues exerted strong and naloxone-resistant inhibition of electrically evoked contractions of rat vas deferens. Lys replacement with Orn maintained or even enhanced the inhibitory activity, while replacements with Dab and Dap decreased inhibitory activity.


Subject(s)
Opioid Peptides/chemical synthesis , Opioid Peptides/pharmacology , Peptide Fragments/chemical synthesis , Peptide Fragments/pharmacology , Opioid Peptides/chemistry , Peptide Fragments/chemistry , Receptors, Opioid/drug effects
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