[Chemical reaction: see text] A modular total synthesis of lamellarin D, a marine alkaloid with potent cytotoxic as well as topoisomerase I inhibition properties, has been accomplished. A sequential and regioselective bromination/Suzuki cross-coupling procedure was applied for the introduction of aryl groups at positions 1 and 2 of scaffold 1. Microwave-assisted 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) oxidation to yield pyrroloisoquinoline 15, followed by phenol group deprotection and subsequent lactonization, gave lamellarin D (18% in eight steps from 1).
The structures of eight 2,4,6-trisubstituted-5-nitrosopyrimidines (one of which crystallizes in two polymorphs) have been determined, including seven O6-benzyl derivatives which are potential, or proven, in vitro inhibitors of the human DNA-repair protein O6-alkylguanine-DNA-transferase. In the derivatives having an amino substituent at the 4-position, an intramolecular N—H...O hydrogen bond with the nitroso O as an acceptor leads to an overall molecular shape similar to that of substituted purines. There is a marked propensity for these nitroso compounds to crystallize with Z′ = 2. The structure of an analogue with no nitroso group is also reported for comparative purposes. Compounds containing the N-alkyl substituents —NHCH2COOEt, —NHCH2CH2COOEt and —NHCH(CH2Ph)COOEt, derived from amino acid esters, exhibit a rich variety of conformational behaviour, and in all of the nitroso compounds the bond lengths provide strong evidence for a highly polarized electronic structure. Associated with this polarization is extensive charge-assisted hydrogen bonding between the molecules, leading to supramolecular aggregation in the form of finite (zero-dimensional) aggregates, chains, molecular ladders, sheets and frameworks.
The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogues of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB-231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data, the SAR study concluded that more than 75% of the open-chain Lam-D analogues tested showed cytotoxicity in a low micromolar GI50 range.
The structures of six symmetrically 4,6-disubstituted 2-aminopyrimidines, four of them containing a 5-nitroso substituent, have been determined. The nitroso compounds, in particular, exhibit polarized molecular-electronic structures leading to extensive charge-assisted hydrogen bonding. The intermolecular interactions observed include hard hydrogen bonds of N-H...N and N-H...O types together with O-H...O and O-H...N types in 2-amino-4,6-bis(2-hydroxyethylamino)-5-nitrosopyrimidine; soft hydrogen bonds of the C-H...O type in both 2-amino-4,6-bis(morpholino)-5-nitrosopyrimidine (3) and 2-amino-4,6-bis(benzylamino)-5-nitrosopyrimidine (4), and of the C-H...pi(arene) type in both 2-amino-4,6-bis(piperidino)pyrimidine (1) and 2-amino-5-nitroso-4,6-bis(3-pyridylmethoxy)pyrimidine (5); and aromatic pi...pi stacking interactions in 2-amino-5-nitroso-4,6-bis(3-pyridylmethoxy)pyrimidine. The supramolecular structures formed by the hard hydrogen bonds are finite, zero-dimensional in (1), one-dimensional in 2-amino-4,6-bis(3-pyridylmethoxy)pyrimidine (2), two-dimensional in both (3) and (4), and three-dimensional in both (5) and 2-amino-4,6-bis(2-hydroxyethylamino)-5-nitrosopyrimidine.
Molecules of 2-amino-4,6-dimethoxypyrimidine, C(6)H(9)N(3)O(2), (I), are linked by two N-H.N hydrogen bonds [H.N 2.23 and 2.50 A, N.N 3.106 (2) and 3.261 (2) A, and N-H.N 171 and 145 degrees ] into a chain of fused rings, where alternate rings are generated by centres of inversion and twofold rotation axes. Adjacent chains are linked by aromatic pi-pi-stacking interactions to form a three-dimensional framework. In 2-benzylamino-4,6-bis(benzyloxy)pyrimidine, C(25)H(23)N(3)O(2), (II), the molecules are linked into centrosymmetric R(2)(2)(8) dimers by paired N-H.N hydrogen bonds [H.N 2.13 A, N.N 2.997 (2) A and N-H.N 170 degrees ]. Molecules of 2-amino-4,6-bis(N-pyrrolidino)pyrimidine, C(12)H(19)N(5), (III), are linked by two N-H.N hydrogen bonds [H.N 2.34 and 2.38 A, N.N 3.186 (2) and 3.254 (2) A, and N-H.N 163 and 170 degrees ] into a chain of fused rings similar to that in (I).
Several alkoxy‐5‐nitrosopyrimidines were synthesised and high regioselective and sequential nucleophilic aromatic substitution of methoxy groups in 2‐amino‐4,6‐dimethoxy‐5‐nitrosopyrimidine was observed. The approach was applied to the synthesis of valuable polyfunctionalised aminopyrimidines capable of mimicking fused heterobicyclic derivatives of biological interest. In addition, new compounds were evaluated as antivirals and their usefulness as synthetic intermediates was demonstrated.
Sphingosine-1-phosphate is now emerging as an important player in cancer, inflammation, autoimmune, neurological and cardiovascular disorders. Abundance evidence in animal and humans cancer models has shown that SphK1 is linked to cancer. Thus, there is a great interest in the development new SphK1 inhibitors as a potential new treatment for cancer. In a search for new SphK1 inhibitors we selected the well-known SKI-II inhibitor as the starting structure and we synthesized a new inhibitor structurally related to SKI-II with a significant but moderate inhibitory effect. In a second approach, based on our molecular modeling results, we designed new structures based on the structure of PF-543, the most potent known SphK1 inhibitor. Using this approach, we report the design, synthesis and biological evaluation of a new series of compounds with inhibitory activity against both SphK1 and SphK2. These new inhibitors were obtained incorporating new connecting chains between their polar heads and hydrophobic tails.On the other hand, the combined techniques of molecular dynamics simulations and QTAIM calculations provided complete and detailed information about the molecular interactions that *
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