I03-Macromolecular Crystallography
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Diamond Proposal Number(s):
[34035]
Open Access
Abstract: The discovery of tubulysins sparked considerable interest due to their high cytotoxic activity against multidrug resistant tumors. Total synthesis of these complex natural products—peptidic metabolites from myxobacteria Archangium gephyra and Angiococcus disciformis—demonstrated the power of organic chemistry and paved the way for the development of simpler, more stable, and selective derivatives. Despite these significant achievements, tubulysins are not used as stand-alone drugs due to their toxic side effects. In this study, we outline the design, synthesis, and evaluation of photoswitchable tubulysin analogues, which could be starting points for development of photopharmacological therapies aimed at addressing the toxicity challenges associated with tubulysins. The cytotoxic activity of one of the key analogues was shown to be light-controllable. For the first time, we provide a comparative analysis of the crystal structures of both photoisomers of a diarylethene-containing compound complexed with target proteins. This comparison enables a mechanistic explanation for the experimentally observed differences in the target binding efficiency and respective activity between the two photoisomers of the photoswitchable tubulysin analogue.
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Aug 2026
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B23-Circular Dichroism
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Carolina
Díaz-Norambuena
,
Juan Manuel
Moreno-Naranjo
,
David
Reger
,
Giuliano
Siligardi
,
César
Ray
,
Jessica
Colligan
,
Florencio
Moreno
,
Beatriz L.
Maroto
,
Gilles
Muller
,
Jorge
Bañuelos
,
Matthew J.
Fuchter
,
Santiago De La
Moya
Open Access
Abstract: Chiral organic thin films are emerging as key materials in advanced optoelectronic and chiroptical technologies, where the straightforward, solution-processed fabrication of chiroptically active neat films from small π-conjugated helical molecules is highly desirable for sustainable and scalable device integration. However, in such densely packed systems, the intrinsic chiroptical response is often compromised by macroscopic anisotropies (e.g., linear dichroism and birefringence) and aggregation-induced effects, which obscure genuine molecular signatures and induce or alter chiral exciton coupling. Here, we demonstrate that a readily accessible and conformationally flexible helically chiral boron-dipyrromethene dimer (helicoBODIPY) platform enables the reproducible fabrication of robust solution-processed neat thin films exhibiting a unique behavior: chiroptical isotropy while retaining the characteristic molecular chiroptical response arising from intramolecular chiral exciton coupling. Through systematic structural tuning, these systems exhibit enhanced electronic circular dichroism (ECD) and circularly polarized luminescence in solution. Remarkably, the sharp ECD couplets and absorption dissymmetry values measured in the corresponding films closely reproduce those observed in solution, indicating minimal contribution from anisotropic contributions and negligible perturbation of excitonic interactions in the condensed phase. These unique findings point to helically flexible helicoBODIPYs as an excellent molecular platform that bridges molecular design and thin-film performance, offering a potential tool for disentangling aggregation effects in chiral thin films and advancing the rational design of chiral organic materials with predictable chiroptical properties.
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Aug 2026
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Xinyu
Wang
,
William T. W.
Butler
,
James R.
Donald
,
Yuran
Wang
,
Alice L.
Shaw
,
Marion
Schuller
,
Daren
Fearon
,
Jasmin C.
Aschenbrenner
,
Peter G.
Marples
,
Grant
Watt
,
Yang
Lu
,
Simon C. C.
Lucas
,
Silvia
Bonomo
,
Jennifer E.
Nelson
,
Ivan
Ahel
,
Frank
Von Delft
,
Peter
O'Brien
Diamond Proposal Number(s):
[27001]
Open Access
Abstract: Mac1 is a conserved macrodomain enzyme in the nonstructural protein 3 (Nsp3) of SARS-CoV-2 and is part of the viral replication machinery. Mac1 is a target for small-molecule inhibitors that could ultimately enable new COVID-19 therapeutics to be developed. Here, we report the structure-guided design, synthesis, and Mac1 inhibition profiling of 25 analogues derived from a hit identified through crystallographic fragment screening. The heteroaryl group and scaffold (cis- and trans-cyclopentane and cyclopentene) were varied. Two new approaches to trans-cyclopentanes were developed: MacMillan’s Ir/Ni-mediated photoredox cross-coupling of alcohols and Barluenga–Valdés’ metal-free cross-coupling of sulfonyl hydrazones and boronic acids. X-ray crystal structures of 19 compounds bound to Mac1 were determined to guide the design and to rationalize the observed SAR. A new family of Mac1 inhibitors with benzothiazole or amino benzothiazoles was discovered and characterized, with IC50 values of 6–8 μM and ligand efficiency values of up to 0.40.
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Jul 2026
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I07-Surface & interface diffraction
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Diamond Proposal Number(s):
[36456]
Open Access
Abstract: Vacuum-deposited organic solar cells (OSCs) have lagged behind their solution-processed counterparts in achieving high power conversion efficiency (PCE), in particular as result of higher voltage losses. In this study, we demonstrate a bulk heterojunction OSC using SubNc as donor and DCV3T as non-fullerene acceptor, achieving a PCE of 2.6% and a remarkably low total voltage loss of 0.64 V, lower than the typical values exceeding 0.7 V observed in vacuum thermally evaporated fullerene-based systems. The device also exhibits non-radiative voltage losses comparable to leading non-fullerene-acceptor (NFA) based OSCs. Transient absorption spectroscopy confirms efficient Förster resonance energy transfer from DCV3T to SubNc, followed by electron transfer for exciton separation. Morphological Grazing Incidence Wide-Angle X-ray Scattering features suggest both blends have a preferential edge-on orientation of DCV3T molecules, and the blends with higher DCV3T content could suffer from suppressed out-of-plane lamellar crystallinity with possible connection with greater non-radiative losses. Our findings demonstrate the potential of designing low-voltage-loss evaporated OSCs by building on strategies from solution-processed NFA systems, while highlighting the continued need for new evaporable acceptors with optimised optoelectronic and morphological properties.
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Jul 2026
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I11-High Resolution Powder Diffraction
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Francesco
Mele
,
Ana M.
Constantin
,
Marco
Barezzi
,
Leonardo
Rossi
,
Alex
Ergasti
,
Tomaso
Fontanini
,
Sofia
Civardi
,
Remie M.
Sundermann
,
Paolo P.
Mazzeo
,
Raimondo
Maggi
,
Nicola
Della Ca'
,
Andrea
Prati
,
Luca
Capaldo
Diamond Proposal Number(s):
[40262]
Open Access
Abstract: The Johnson-Corey-Chaykovsky reaction stands as an elegant approach for the synthesis of cyclopropanes and epoxides. However, most procedures still rely on the original NaH/DMSO conditions, which pose notable safety and handling issues especially in view of industrial applications. Herein, we combine Bayesian Optimization and mechanochemistry to develop a rapid, solvent-free protocol for the Johnson-Corey-Chaykovsky reaction. By prioritizing efficiency and sustainability, Machine Learning quickly identified a new set of reaction conditions for this transformation, also demonstrating that these transformations can proceed efficiently under air-equilibrated, mild conditions using an inexpensive and safe base (KOH). The method is broadly applicable, scalable, and tolerant to diverse functional groups and enabled the preparation of a wide variety of three-membered homo- and heterocycles. Time-Resolved in situ X-ray Powder Diffraction experiments highlighted the crucial role of active milling in promoting this transformation. Overall, this work establishes a foundation for the integration of Machine Learning and mechanochemistry in designing industrially relevant transformations that prioritize safety and sustainability.
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Jul 2026
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I03-Macromolecular Crystallography
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Spencer O.
Scholz
,
Alexander S.
Dudnik
,
Aristidis
Vasilopoulos
,
Zhaozhong J.
Jia
,
Anna
Albertson
,
Brian S.
Brown
,
Liye
Chen
,
Renhe
Li
,
Gaoyuan
Ma
,
Longcheng
Wang
,
Akinori
Okano
,
Xianrui
Zhao
,
Xingyu
Jiang
,
Caleb
Karmel
,
Patrick B.
Brady
,
Chunqiu
Lai
,
Hemantkumar
Deokar
,
Felix
Deanda
,
Somdutta
Roy
,
Manasi
Mayekar
,
Hana
Choi
,
Louis
Lin
,
David G.
Belair
,
Anand
Joshi
,
Woo Hyun
Yoon
,
Andrea
Montano
,
Xiaoping
Xie
,
Henry
Nguyen
,
Haiyan S.
Li
,
Chin
Pan
,
Ben
Danna
,
Deepak
Gurbani
,
Jingzhi
Li
,
Alla
Korepanova
,
Tao
Li
,
Tarikere
Gururaja
,
Rong-Xian
Ding
,
Rinku
Jain
,
Ruth L.
Martin
,
Rebecca
Kohnken
,
Alexey
Rivkin
Abstract: Decapping Scavenger (DcpS) enzyme, a pyrophosphatase involved in mRNA regulation via mRNA cap degradation, has been identified as a promising oncology target in fragile histidine triad (FHIT) deficient cancers such as AML and GBM but remains underexplored in broader solid tumor indications. We have discovered a novel DcpS inhibitor, compound 17, which has a differentiated binding mode relative to known inhibitors, engaging the second nucleotide-binding domain of the mRNA cap substrate. Compound 17 possesses superior levels of potency in NSCLC A549 cell line relative to known inhibitors and demonstrates excellent selectivity against DcpS-insensitive cell lines, high levels of bioavailability in preclinical species, and mitigated hERG liabilities. Finally, compound 17 demonstrates oral dose-dependent efficacy in two solid tumor xenograft models, A253 and EBC-1, highlighting the promise of DcpS as a novel target in FHIT low/deficient solid tumors.
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Jul 2026
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I04-Macromolecular Crystallography
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Kathryn A.
Giblin
,
Kun
Song
,
Hongming
Chen
,
Weijie
Chen
,
Zhiqiang
Dong
,
Randolph A.
Escobar
,
Tyler P.
Grebe
,
Neil P.
Grimster
,
Alexander W.
Hird
,
Samantha J.
Hughes
,
Jason G.
Kettle
,
Chengzhi
Li
,
Hao
Ma
,
Alexander
Pflug
,
Magdalena
Richter
,
Marianne
Schimpl
,
Haoran
Tang
,
Peng
Wang
,
Gail
Wrigley
,
Ye
Wu
,
Haichang
Yu
,
Robert E.
Ziegler
,
Jason D.
Shields
Diamond Proposal Number(s):
[20015]
Abstract: Generative artificial intelligence (AI) is now widely applied in medicinal chemistry, with detailed case studies emerging in the literature. Here, we describe an early application of REINVENT, AstraZeneca’s in-house generative molecular design platform, to identify new inhibitor scaffolds for hematopoietic progenitor kinase 1 (HPK1). REINVENT was deployed at two stages of the project to address distinct design objectives. For hit identification, transfer learning on kinase-active compounds, followed by reinforcement learning guided by QSAR-based scoring, led to the discovery of three active chemotypes. Subsequently, REINVENT was applied to scaffold hopping, using 3D pharmacophore and docking models as scoring functions, which enabled the identification of two additional active chemotypes. Optimization of one of these scaffolds delivered a compound with potent cellular activity, kinase selectivity, and favorable rat pharmacokinetics. These results demonstrate the value of integrating generative AI with medicinal chemistry expertise and support broader application of the approach in future discovery programs.
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Jul 2026
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[41089]
Open Access
Abstract: Antiaromatic compounds are often difficult to work with due to their relative instability in comparison with aromatic analogues. As a consequence, their application in functional materials remains in its infancy. Here, we report the synthesis of porous MII4L6 (M = Fe, Zn) coordination cages equipped with dibenzo[a,e]pentalene panels involving the antiaromatic motif of pentalene stabilized by benzannulation. Both cages encapsulate fullerene C60, with the more adaptable zinc(II) cage also binding C70, undergoing pronounced structural reconfiguration upon C60 inclusion, and displaying broader affinity for polycyclic aromatic hydrocarbons. The cages selectively bind anthraquinone over its reduced form and interact with steroids such as testosterone and cholesterol. Remarkably, the chemical shifts of the guests are affected by the aromatic Clar sextets rather than the antiaromatic pentalene motif. These assemblies represent only the second reported example of a supramolecular cage with a cavity fully enclosed by antiaromatic walls and demonstrate that benzannulated antiaromatic motifs can be incorporated into cages without interrupting conventional host–guest behavior, while simultaneously allowing for a systematic tuning of magnetic shielding effects.
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Jul 2026
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I03-Macromolecular Crystallography
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Diamond Proposal Number(s):
[31850]
Open Access
Abstract: Developing enzymatic strategies to selectively construct C–C and C–heteroatom bonds is a major objective in modern biocatalysis. Here we combine genetic code reprogramming and laboratory evolution to establish a family of allylic transferase enzymes that can achieve a remarkable breadth of chemistry, enabling the generation of valuable motifs including γ‑butenolides, chiral amines and all-carbon quaternary centres. Our enzymes operate through the formation of electrophilic imidazolium intermediates that can be generated from reagents equipped with a para-nitrophenol leaving group to facilitate high-throughput evolution. These intermediates can be intercepted with diverse carbon and nitrogen nucleophiles to generate densely functionalized products featuring Cβ or Cγ stereocentres. Interestingly, structural analysis suggests that catalysis proceeds through an unanticipated ternary complex involving para-nitrophenol and the incoming substrate nucleophile. This study adds a family of C–C and C–N bond-forming enzymes to the biocatalytic repertoire and illustrates how artificial enzymes can achieve precise control over challenging chemical conversions.
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Jul 2026
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B23-Circular Dichroism
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Diamond Proposal Number(s):
[36727]
Open Access
Abstract: We report a new chiral indaceno[1,2-b:5,6-b′]dithiophene bis-thiophenylpropynone (IDT-TPO) dye exhibiting very noticeable chiroptical properties in thin films. While freshly prepared samples are ECD-silent, aging triggers a giant dichroic response, with ellipticity values reaching approximately 18,000 mdeg, among the highest reported to date for thin films of chiral organic dyes as neat materials. This amplification is accompanied by an unusual flattening of the main UV-Vis absorption band, and the combination of these effects produces very large gabs values (exceeding 0.1). A thorough investigation, combining microscopy and spatially resolved chiroptical techniques with time-dependent density functional theory (TD-DFT) calculations, reveals that the intense chiroptical activity arises primarily from the consistent formation of right-handed three-dimensional (3D) helical architectures. Notably, the degree of circular polarization exhibits a non-monotonic dependence on film thickness: the maximum ECD intensity was found for a thinner film, rather than for the thickest one. This behavior is particularly promising for optoelectronic applications requiring efficient chiroptical responses in relatively thin active layers.
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Jul 2026
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