Toward a Rational Design of Polyamine-Based Zinc-Chelating Agents for Cancer Therapies

Abstract

In vitro viability assays against a representative panel of human cancer cell lines revealed that polyamines L1a and L5a displayed remarkable activity with IC50 values in the micromolar range. Preliminary research indicated that both compounds promoted G1 cell cycle arrest followed by cellular senescence and apoptosis. The induction of apoptotic cell death involved loss of mitochondrial outer membrane permeability and activation of caspases 3/7. Interestingly, L1a and L5a failed to activate cellular DNA damage response. The high intracellular zinc-chelating capacity of both compounds, deduced from the metal-specific Zinquin assay and ZnL 2+ stability constant values in solution, strongly supports their cytotoxicity. These data along with quantum mechanical studies have enabled to establish a precise structure–activity relationship. Moreover, L1a and L5a showed appropriate drug-likeness by in silico methods. Based on these promising results, L1a and L5a should be considered a new class of zinc-chelating anticancer agents that deserves further development.

New Triazacycloalkane Derivatives as Cytotoxic Agents for CLL Treatment: From Proof of Concept to the Targeting Biomolecule

“…The conjugation implies the reaction between the carboxylic acid function of no3pyCOOK and the primary amine function of the sialoglycan (10). The peptidic coupling was carried out with the usual method using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl) and hydrox- ybenzotriazole (HOBt) coupling agents to afford the protected bioconjugate (11). Hydrolysis of the acetate and methyl ester functions in (11) using sodium methoxide in methanol and potassium carbonate allowed one to obtain the expected bioconjugated 6′-SL-no3py (Scheme 3).…”

“…Phases were separated, the organic layer was dried over MgSO 4 , and solvents were evaporated to dryness. Purification of the residue by column chromatography over silica gel (eluent: CH 2 Cl 2 / MeOH 100/0 to 100/3.5) gave compound (11) (145 mg, 0.09 mmol, 56%) as a yellow solid. 1 H NMR (500 MHz, CDCl 3 , 298 K) δ (ppm): 8.48 (s, 2H, H31), 8.39 (d, J = 4.9 Hz, 1H, H19), 7.62 (t, J = 7.1 Hz, 2H, H29), 7.50 (d, J = 7.7 Hz, 3H, H20, H28), 7.12 (m, 3H, H18, H30), 5.61 (d, J H1−H2 = 5.0 Hz, 1H, H1), 5.45 (s, 1H, H3), 5.41 (d, J H3′−H4′ = 2.6 Hz, 1H, H4′), 5.33−5.27 (m, 1H, H8″), 5.24 (d, J = 9.2 Hz, 1H, H7″), 5.11 (dd, J H2′−H1′ = 8.2 Hz, J H2′−H3′ = 10.2 Hz, 1H, H2′), 5.01 (dd, J H3′−H4′ = 3.3 Hz, J H2′−H3′ = 10.4 Hz, 1H, H3′), 4.84 (ddd, J H3″eq−H4″ = 4.7 Hz, J H3″ax−H4″ = 12.0 Hz, 1H, H4″), 4.66 (d, J H1′−H2′ = 7.9 Hz, 1H, H1′), 4.28 (dd, J = 2.0, 12.2 Hz, 1H, H9″a), 4.25 (m, 2H, H2, H6a), 4.14−3.84 (m, 11 H, H6b, H6″, H9″b, H5′, H5″, H22, H26), 3.81−3.79 (m, 1H, H5), 3.79 (s, 3H, COOCH 3 ), 3.72 (d, J H4−H5 = 9.9 Hz, 1H, H4), 3.64 (dd, J H5′−H6′a = 6 Hz, J H6′a−H6′b = 10.8 Hz, 1H, H6′a), 3.52 (m, 2H, H9), 3.38 (m, 3H, H10, H6′b), 2.93 (br s, 12H, H23, H24, H25), 2.53−2.43 (m, 3H, H3″a, H14), 2.33 (m, 2H, H12), 2.15 (s, 3H, CH 3 OAc), 2.11 (s, 3H, CH 3 OAc), 2.07 (s, 9H, CH 3 OAc), 2.02 (s, 3H, CH 3 OAc), 2.00 (s, 3H, CH 3 OAc), 1.98 (s, 3H, CH 3 OAc), 1.92 (m, 5H, CH 3 OAc +H13), 1.85 (m, 4H, CH 3 NHAc + H3″ax), 1.66 (s, 3H, H8).…”

“…Parent linear triamine derivatives with 2-methylpyridine N-substituents have also recently exhibited cytotoxic properties on cancer cells. 11 In these different studies, these polyamines role in caspase activation and subsequent apoptosis induction has been suggested to be related to Zn 2+ chelation or oxidative stress. 8−11 Interestingly, despite their well-known astonishing complexing properties, polyazacycloalkanes, which are the cyclic analogues of the TPEN backbone, have not been investigated in this area.…”

“…Indeed, N , N , N ′, N ′-tetrakis­(2-pyridylmethyl)­ethylenediamine ( TPEN ) (Chart ), an “open-chain” tetraamine N -functionalized by 2-methylpyridine chelating groups, has shown high cytotoxicity and activity in producing apoptosis in K562 cells, in acute lymphoblastic leukemia cells, and in cancer cells by generating zinc depletion. Parent linear triamine derivatives with 2-methylpyridine N -substituents have also recently exhibited cytotoxic properties on cancer cells . In these different studies, these polyamines role in caspase activation and subsequent apoptosis induction has been suggested to be related to Zn 2+ chelation or oxidative stress. − …”

Ditopic Aza-Scorpiand Ligands Interact Selectively with ds-RNA and Modulate the Interaction upon Formation of Zn2+ Complexes

“…For instance, Futaki and co-workers described as Co 2+ coordination to some peptide dimeric systems containing iminodiacetic acid groups decreases their structural helical arrangement reducing thereby, their interaction with DNA [ 11 ]. In this line, our group is devoted to the development of polyamine-based systems because they present interesting structural features for modulating the binding of anionic species, in particular, ( i ) the significant changes in net charge within short pH ranges [ 12 ] and ( ii ) the ability to strongly coordinate metal ions [ 13 , 14 ].…”