Amidine Analogues of Melphalan: Synthesis, Cytotoxic Activity, and DNA Binding Properties

Bielawska, Anna; Bielawski, Krzysztof; Anchim, Tomasz

doi:10.1002/ardp.200700001

Cited by 12 publications

(4 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There have also been reports in the literature that esterification can increase bioavailability and cellular penetration [21][22][23][24]. In addition, other in vitro studies have shown that amidine analogs of melphalan reduce the number of estrogen receptor-positive and estrogen receptor-free breast cancer cells [25,26].…”

Section: Discussionmentioning

confidence: 99%

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Poczta

Krzeczyński

Tobiasz

et al. 2022

IJMS

View full text Add to dashboard Cite

Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM–T–MEL), indoline (EM–I–MEL), or 4–(4–morpholinyl) piperidine (EM–MORPIP–MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC–1 (5,5′,6,6′–tetrachloro–1,1′,3,3′–tetraethylbenzimidazol carbocyanine). The EM–T–MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure–biological activity analyses.

show abstract

Section: Discussionmentioning

confidence: 99%

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Poczta

Krzeczyński

Tobiasz

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…These new amidine analogues of bis(2-chloroethyl)amine 7 -12 differing by the nature of their terminal basic side chains were isolated as the hydrochloride salts. The structures of compounds 7 -12 have been proven by 1 H-NMR, 13 C-NMR, and elemental analysis.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Cytotoxic Activity of Novel Amidine Analogues of Bis(2‐chloroethyl)amine

Bielawski

Bielawska

Popławska

2009

Archiv der Pharmazie

Self Cite

View full text Add to dashboard Cite

Novel nitrogen mustard agents 7-12 involving 4-(N,N-bis(2-chloroethyl)aminophenyl)propylamine linked to a 5-(4-N-alkylamidinophenyl)-2-furancarboxylic acid moiety by the formation of an amide bond have been synthesized, characterized, and evaluated for their in-vitro cytotoxic activity against MDA-MB-231 and MCF-7 human breast cancer cells. Evaluation of the cytotoxicity of 7-12 employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA demonstrated that these compounds exhibit remarkable cytotoxic effects in comparison with 4-[bis(2-chloroethyl)amino]benzenebutanoic acid. Compounds 7 and 9, which possess a cationic amidine and 4,5-dihydro-1H-imidazol function moiety are approximately ten times more potent than 4-[bis(2-chloroethyl)amino]benzenebutanoic acid. The new compounds were evaluated as DNA topoisomerase II inhibitors. The cytotoxicity of the compounds 7-12 correlates with their DNA-binding affinities and their relative potency as topoisomerase II inhibitors.

show abstract

“…It is known that the major site of the alkylation of melphalan is guanine N7 in the major groove [28]. Studies by Bielawska et al have shown that amidine analogs of melphalan bound to AT-rich sequences in the minor grooves [29].…”

Section: Discussionmentioning

confidence: 99%

Newly Synthesized Melphalan Analogs Induce DNA Damage and Mitotic Catastrophe in Hematological Malignant Cancer Cells

Poczta

Krzeczyński²,

Йонов³

et al. 2022

IJMS

View full text Add to dashboard Cite

Myeloablative therapy with highdoses of the cytostatic drug melphalan (MEL) in preparation for hematopoietic cell transplantation is the standard of care for multiple myeloma (MM) patients. Melphalan is a bifunctional alkylating agent that covalently binds to nucleophilic sites in the DNA and effective in the treatment, but unfortunately has limited therapeutic benefit. Therefore, new approaches are urgently needed for patients who are resistant to existing standard treatment with MEL. Regulating the pharmacological activity of drug molecules by modifying their structure is one method for improving their effectiveness. The purpose of this work was to analyze the physicochemical and biological properties of newly synthesized melphalan derivatives (EE-MEL, EM-MEL, EM-MOR-MEL, EM-I-MEL, EM-T-MEL) obtained through the esterification of the carboxyl group and the replacement of the the amino group with an amidine group. Compounds were selected based on our previous studies for their improved anticancer properties in comparison with the original drug. For this, we first evaluated the physicochemical properties using the circular dichroism technique, then analyzed the zeta potential and the hydrodynamic diameters of the particles. Then, the in vitro biological properties of the analogs were tested on multiple myeloma (RPMI8226), acute monocytic leukemia (THP1), and promyelocytic leukemia (HL60) cells as model systems for hematological malignant cells. DNA damage was assessed by immunostaining γH2AX, cell cycle distribution changes by propidium iodide (PI) staining, and cell death by the activation of caspase 2. We proved that the newly synthesized derivatives, in particular EM-MOR-MEL and EM-T-MEL, affected the B-DNA conformation, thus increasing the DNA damage. As a result of the DNA changes, the cell cycle was arrested in the S and G2/M phases. The cell death occurred by activating a mitotic catastrophe. Our investigations suggest that the analogs EM-MOR-MEL and EM-T-MEL have better anti-cancer activity in multiple myeloma cells than the currently used melphalan.

show abstract

Amidine Analogues of Melphalan: Synthesis, Cytotoxic Activity, and DNA Binding Properties

Cited by 12 publications

References 21 publications

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Synthesis and Cytotoxic Activity of Novel Amidine Analogues of Bis(2‐chloroethyl)amine

Newly Synthesized Melphalan Analogs Induce DNA Damage and Mitotic Catastrophe in Hematological Malignant Cancer Cells

Contact Info

Product

Resources

About