New dipeptide derivatives 1 and 3 were synthesized and their reactivity in the photochemical reaction of decarboxylation was investigated. The photodecarboxylation of N-adamantyl derivatives 1a and ...1b and N-phenylphthalimide derivatives 3a and 3b probably takes place from the triplet excited state. The triplet excited state of 1a, 3a and 3b was characterized by laser flash photolysis. N-phenylphthalimides 3a and 3b undergo 2-5 times more efficient photodecarboxylation than N-adamantylphthalimides 1a and 1b. The aminoacid residue (Phe or Gly) at the C-terminus of the dipeptide does not influence the photodecarboxylation efficiency. Product selectivity in the photoreactions is determined by the conformation of the molecules. N-phenylphthalimides with the separated electron donor (carboxylate) and acceptor moiety (phthalimide) give only simple decarboxylation products, whereas N-adamantyl derivatives also give cyclization products. Keywords: photodecarboxylation, dipeptides, phthalimides
We have demonstrated that quinone methide (QM) precursors can be introduced in the peptide structure and used as photoswitchable units for peptide modifications. QM precursor 1 was prepared from ...protected tyrosine in the Mannich reaction, and further used as a building block in peptide synthesis. Moreover, peptides containing tyrosine can be transformed into a photoactivable QM precursor by the Mannich reaction which can afford monosubstituted derivatives 2 or bis-substituted derivatives 3. Photochemical reactivity of modified tyrosine 1 and dipeptides 2 and 3 was studied by preparative irradiation in CH
OH where photodeamination and photomethanolysis occur. QM precursors incorporated in peptides undergo photomethanolysis with quantum efficiency Φ
= 0.1-0.2, wherein the peptide backbone does not affect their photochemical reactivity. QMs formed from dipeptides were detected by laser flash photolysis (λ
≈ 400 nm, τ = 100 μs-20 ms) and their reactivity with nucleophiles was studied. Consequently, QM precursors derived from tyrosine can be a part of the peptide backbone which can be transformed into QMs upon electronic excitation, leading to the reactions of peptides with different reagents. This proof of principle showing the ability to photochemically trigger peptide modifications and interactions with other molecules can have numerous applications in organic synthesis, materials science, biology and medicine.
18-crown-6 ethers are known to exert their biological activity by transporting K
+ ions across cell membranes. Using non-linear Support Vector Machines regression, we searched for structural features ...that influence antiproliferative activity in a diverse set of 19 known oxa-, monoaza- and diaza-18-crown-6 ethers. Here, we show that the logP of the molecule is the most important molecular descriptor, among ∼1300 tested descriptors, in determining biological potency (
R
2
cv = 0.704). The optimal logP was at 5.5 (Ghose-Crippen ALOGP estimate) while both higher and lower values were detrimental to biological potency. After controlling for logP, we found that the antiproliferative activity of the molecule was generally not affected by side chain length, molecular symmetry, or presence of side chain amide links. To validate this QSAR model, we synthesized six novel, highly lipophilic diaza-18-crown-6 derivatives with adamantane moieties attached to the side arms. These compounds have near-optimal logP values and consequently exhibit strong growth inhibition in various human cancer cell lines and a bacterial system. The bioactivities of different diaza-18-crown-6 analogs in
Bacillus subtilis and cancer cells were correlated, suggesting conserved molecular features may be mediating the cytotoxic response. We conclude that relying primarily on the logP is a sensible strategy in preparing future 18-crown-6 analogs with optimized biological activity.
Among a variety of molecular descriptors tested, the logP was found to have the prominent role in determining biological activity of oxa-, monoaza- and diaza-18-crown-6 ether derivatives. Six novel adamantane-substituted compounds had logP values close to the optimum of 5.5 and were accordingly highly active against cancer cell lines.
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► Which structural features influence antitumor activity in 18-crown-6 ethers? ► LogP is the most important molecular descriptor (out of 1300) for determining potency. ► To validate the QSAR model six novel highly lipophilic derivatives were prepared. ► Novel molecules exhibit strong growth inhibition in cancer cell lines and bacteria. ► Activities of diaza-18-crown-6 in
B. subtilis and cancer cells were correlated.
We have demonstrated that quinone methide (QM) precursors can be introduced in the peptide structure and used as photoswitchable units for peptide modifications. QM precursor
1
was prepared from ...protected tyrosine in the Mannich reaction, and further used as a building block in peptide synthesis. Moreover, peptides containing tyrosine can be transformed into a photoactivable QM precursor by the Mannich reaction which can afford monosubstituted derivatives
2
or bis-substituted derivatives
3
. Photochemical reactivity of modified tyrosine
1
and dipeptides
2
and
3
was studied by preparative irradiation in CH
3
OH where photodeamination and photomethanolysis occur. QM precursors incorporated in peptides undergo photomethanolysis with quantum efficiency
Φ
R
= 0.1-0.2, wherein the peptide backbone does not affect their photochemical reactivity. QMs formed from dipeptides were detected by laser flash photolysis (
λ
max
400 nm,
τ
= 100 μs-20 ms) and their reactivity with nucleophiles was studied. Consequently, QM precursors derived from tyrosine can be a part of the peptide backbone which can be transformed into QMs upon electronic excitation, leading to the reactions of peptides with different reagents. This proof of principle showing the ability to photochemically trigger peptide modifications and interactions with other molecules can have numerous applications in organic synthesis, materials science, biology and medicine.
We have demonstrated that quinone methide (QM) precursors can be introduced in the peptide structure and used as photoswitchable units for peptide modifications.
Lipophilic disalicylic acids 5,5′-decyl-2,2′-1,2-ethanediylbis(oxy)bisbenzoic acid (
1), 5,5′-decyl-2,2′-1,3-propanediylbis(oxy)bisbenzoic acid (
2), ...5,5′-decyl-2,2′-oxybis(1,2-ethanediyl-oxy)bisbenzoic acid (
3), 3,5-bis2′-(2″-carboxyphenoxy)ethyl-4-oxahexacyclo-5.4.1.0
2,6.0
3,10.0
5,9.0
8,11dodecane (
4), and 1,3-bis2′-(2″-carboxyphenoxy)ethyladamantane (
5) are evaluated as selective Pb(II) extractants. The solvent extraction of Pb(II) and of Cu(II) from buffered aqueous solutions of varying pH into chloroform by ligands
1–5 is examined in relation to the molecular structure of the dicarboxylic acid extractant. Ligand
1, with an ethylene spacer between two lipophilic salicylic acid units, exhibits excellent extraction selectivity for Pb(II) over Cu(II). Lengthening the spacer in ligands
2 and
3 diminishes both the extraction efficiency and selectivity. Ligands
4 and
5, with rigid spacer units, show significant reductions in both Pb(II) and Cu(II) extraction. Slope analysis reveals that ligand
1 reacts in a 2:1 stoichiometry with Pb(II) in extraction, which differs from the 1:1 stoichiometries for
2 and
3. The differences in the half extraction pH (ΔpH
1/2) values for Pb(II) and Cu(II) extraction are 1.29, 0.49, and 0.48 for
1–
3, respectively.
New
N-adamantylaza-crown ethers
1–
8
have been synthesized and their respective alkali metal picrate extraction profiles have been obtained. These results are compared with the results obtained for ...the parent aza-18-crown-6 and
N-benzylaza-18-crown-6. Among the crown hosts studied,
2
, and
6
, proved to be the best alkali metal picrate extractants and displayed significant levels of complexation with K
+ and Rb
+.
A series of
N-adamantylaza-crown ethers were synthesized and their cation-binding abilities were evaluated.
The synthesis of a novel cage-functionalized cryptand,
5, and the X-ray crystal structure of its 1:1 complex with Na
+, i.e.
4, are reported. Host molecule
5 displays high avidity toward Na
+ and K
+ ...picrates and appears to extract these cations selectively. The X-ray crystal structure of
4 clearly indicates that Na
+ is bonded to all seven Lewis base centers (i.e., nitrogen and oxygen atoms) in the complex. In addition, the corresponding alkali metal picrate extraction profile was obtained for
10, an adamantane-containing analog of
5. With the possible exception of its ability to extract K
+ picrate, there appears to be relatively little difference between the alkali metal picrate extracting capabilities of host molecule
10 and a corresponding monocyclic model system, i.e.,
N,
N′-diethyl-4,13-diaza-18-crown-6 (
6).
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