Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.
The design of new and inexpensive
metal-containing functional materials
is of great interest. Herein is reported a unique thermochromic near-IR
emitting coordination polymer, 3D-[Cu8I8(L1)2]
n
, CP2, which is formed when ArS(CH2)4SAr (L1, Ar = 4-C6H4OMe) reacts with 2 equiv
of CuI in EtCN. In MeCN, CP1 ([Cu4I4(L1)(MeCN)2]
n
, consisting of an alternating [-Cu4I4-L1-Cu4I4-L1-]
n
chain where the Cu4I4 cubane
units bear two metal-bound MeCN molecules, is formed. Heat-driven
elimination of these MeCN’s in solid CP1 also
leads to CP2 through a predisposed organization of the
Cu4I4 units prone to fusion after MeCN eliminations
(i.e., a rare case of template effect). The CP2 structure
exhibits parallel 1D-(Cu8I8)
n
chains, (z-axis; designated 1D-[CuI]
n
) as secondary building units (SBU) held together
by parallel thioether ligands (x,y-axes), forming a nonporous 3D network. The structure of this 1D-[CuI]
n
SBU is unprecedented and consists of a series
of fused and twisted open Cu4I4 cubanes forming
a fused poly(truncated rhombic dodecahedron). Unexpectedly, the compact
3D CP2 exhibits a solid-to-solid phase transition at
100 °C and a hysteresis of ∼20 °C. CP1 emits intensively (298 K: λemi = 564 nm; Φe = 0.35), whereas CP2 presents a strongly red-shifted
weaker emission (298 K: λemi ∼ 740 nm, Φe < 0.0001). Moreover, CP2, which is stable
over long periods of time, exhibits thermochromism where the emission
intensity of the near-IR band decreases significantly at the benefit
of a ligand-centered phosphorescence at 415 nm. Altogether, these
properties listed above make CP2 exceptional. The low-energy
singlet and triplet excited states have been assigned to ligand/metal-to-ligand
charge transfer based on DFT and TD-DFT computations.
Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole-and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.
A systematic chain length variation of the ligand para-MeOC 6 H 4 S-(CH 2 ) m SC 6 H 4 OMe (1 ≤ m ≤ 8) was performed to study its effect on the structures and photophysical properties of the coordination polymers (CP) when reacted with CuI. Indeed, direct correlations are noted between these features and m. When m is an odd number, the secondary building unit is systematically the common closed-cubane Cu 4 I 4 cluster, rendering the material strongly luminescent (i.e., emission quantum yield, Φ e > 20%), and the CP is one-dimensional (1D). However, when m is 2, 4, and 6, the SBUs exhibit rare polymeric motifs of (Cu 2 I 2 ) n : staircase ribbon, fused poly(rhombic pseudo-dodecahedron), and accordion ribbon, respectively, and the emission intensities are either very weak (Φ e < 0.001%) or of medium intensity (Φ e ∼ 10% when m = 6). When m = 8 (i.e. the most flexible chain), the SBU is a closedcubane Cu 4 I 4 and the emission intensity is medium (Φ e ∼ 10%). A special case was observed for m = 3, where a co-crystallization of the molecular cluster Cu 4 I 4 (NCCH 3 ) 4 is observed in the lattice, which turns out to be quite important for the stability of the network.
The complete molecule of the hexametallic title complex, namely, tetrabromidotetra-μ-hydroxido-hexakis[μ-2-methyl-3-(pyrrolidin-1-yl)propan-2-olato]hexazinc(II) acetone disolvate, [Zn6Br4(C9H18NO)4(OH)4]·2C3H6O2, is generated by a crystallographic centre of symmetry. Two of the unique zinc atoms adopt distorted ZnO2NBr tetrahedral coordination geometries and the other adopts a ZnO3N tetrahedral arrangement. Both unique alkoxide ligands are N,O-chelating and both hydroxide ions are μ2 bridging. The crystal structure displays an O—H...O hydrogen bond between a μ2-OH group and an acetone solvent molecule. The Hirshfeld surface has been calculated and is described.
Oxindoles and iso‐oxindoles are natural product‐derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso‐oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective RhIII‐catalyzed scaffold‐divergent synthesis of spirooxindole–isooxindoles and spirooxindole–oxindoles from differently protected diazooxindoles and N‐pivaloyloxy aryl amides which includes a functional group‐controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.
The metalation of N,N‐dimethylaminomethylferrocene in THF by the superbasic mixture of nBuLi/KOtBu proceeds readily at low temperatures to afford a bimetallic Li2K2 aggregate containing ferrocenyl anions and tert‐butoxide. Starting from an enantiomerically enriched ortho‐lithiated aminomethylferrocene, an enantiomerically pure superbase can be prepared. The molecular compound exhibits superbasic behavior deprotonating N,N‐dimethylbenzylamine in the α‐position and is also capable of deprotonating toluene. Quantum chemical calculations provide insight into the role of the bridging THF molecule to the possible substrate–reagent interaction. In addition, a benzylpotassium alkoxide adduct gives a closer look into the corresponding reaction site of the Lochmann–Schlosser base that is reported herein.
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