Modification Of Scaffold Research Articles

The Germline-Restricted Chromosome of Male Zebra Finches in Meiotic Prophase I: A Proteinaceous Scaffold and Chromatin Modifications

Among eukaryotes, there are many examples of partial genome elimination during ontogenesis. A striking example of this phenomenon is the loss of entire avian chromosomes during meiosis, called a germline-restricted chromosome (GRC). The GRC is absent in somatic tissues but present in germ cells. It has been established that a prophase I male GRC is usually represented by a univalent surrounded by heterochromatin. In the present study, an immunocytochemical analysis of zebra finch spermatocytes was performed to focus on some details of this chromosome’s organization. For the first time, it was shown that a prophase I GRC contains the HORMAD1 protein, which participates in the formation of a full axial element. This GRC axial element has signs of a delay of core protein loading, probably owing to peculiarities of meiotic silencing of chromatin. The presence of repressive marks (H3K9me3 and H3K27me3) and the lack of RNA polymerase II, typically associated with active transcription, indicate transcriptional inactivation in the GRC body, despite the known activity of some genes of the GRC. Nevertheless, RPA and RAD51 proteins were found at some GRC sites, indicating the formation and repair of double-strand breaks on this chromosome. Our results provide new insights into the meiotic behavior and structure of a GRC.

Pd/IPrBIDEA‐Catalyzed Synthesis of Pyrroles via Cascade C−C/C−F Cleavage/Annulation of gem‐Difluorocyclopropanes

AbstractA regioselective cascade C−C/C−F cleavage/annulation of gem‐F2CPs with enaminones catalyzed by Pd/IPrBIDEA is reported. The NHC ligand IPrBIDEA plays a pivotal role in enhancing the reaction efficiency. With this protocol, a variety of fully substituted pyrroles were obtained in good to excellent yields. Furthermore, this approach facilitates the modification of some bioactive scaffolds.

A facile nanopattern modification of silk fibroin electrospun scaffold and corresponding impact on cell proliferation and osteogenesis

Abstract As a well-known natural protein biomaterial, silk fibroin (SF) has shown broad application prospects in typical biomedical fields. However, the mostly used SF from Bombyx mori silkworm lacks specific cell adhesion sites and other bioactive peptide sequences, and there is still significant room for further improvement of their biological functions. Therefore, it is crucial to develop a facile and effective modification strategy for this widely researched biomaterial. In this study, the SF electrospun scaffold has been chosen as a typical SF biomaterial, and air plasma etching has been adopted as a facile nanopattern modification strategy to promote its biological functions. Results demonstrated that the plasma etching could feasibly and effectively create nano-island-like patterns on the complex surface of SF scaffolds, and the detailed nanopattern features could be easily regulated by adjusting the etching time. In addition, the mesenchymal stem cell responses have illustrated that the nanopattern modification could significantly regulate corresponding cell behaviors. Compared with the non-etched scaffold, the 10 min-etched scaffold (10E scaffold) significantly promoted stem cell proliferation and osteogenic differentiation. Moreover, 10E scaffold has also been confirmed to effectively accelerate vascularization and ectopic osteogenesis in vivo using a rat subcutaneous implantation model. However, the mentioned promoting effects would be weakened or even counteracted with the increase of etching time. In conclusion, this facile modification strategy demonstrated great application potential for promoting cell proliferation and differentiation. Thus, it provided useful guidance to develop excellent SF-based scaffolds suitable for bone and other tissue engineering.

Evaluation of Quinoline-Related Carboxylic Acid Derivatives as Prospective Differentially Antiproliferative, Antioxidative, and Anti-Inflammatory Agents.

The higher prevalence of cancer and the unmet need for antioxidant/anti-inflammatory chemotherapeutic compounds with little side effect are of utmost importance. In addition, the increased likelihood of failure in clinical trials along with increasing development costs may have diminished the range of choices among newer drugs for clinical use. This has dictated the necessity to seek out novel medications by repurposing as it needs less time, effort, and resources to explore new uses of a current or unsuccessful medication. In this study, we examined the biological activity of 10 potential quinoline derivatives. Given the half-maximal inhibitory concentration (IC50 value) in lipopolysaccharide (LPS) induced inflammation of RAW264.7 mouse macrophages, all commercial FQs and selected quinolines (quinoline-4-carboxlic and quinoline-3-carboxylic acids) exerted impressively appreciable anti-inflammation affinities versus classical NSAID indomethacin without related cytotoxicities in inflamed macrophages. Conversely, all 14 tested compounds lacked antioxidative DPPH radical scavenging capacities as compared to ascorbic acid. Gemifloxacin, considerably unlike markets FQs, indomethacin and quinoline derivatives, exerted exceptional and differential antiproliferation propensities in colorectum SW480, HCT116, and CACO2, pancreatic PANC1, prostate PC3, mammary T47D, lung A375, and melanoma A549 adherent monolayers using the sulforhodamine B colorimetric method versus antineoplastic cisplatin. All quinoline derivatives and gemifloxacin alike, but not levofloxacin, ciprofloxacin, or indomethacin, displayed substantially selective viability reduction affinities in prolonged tumor incubations of cervical HELA and mammary MCF7 cells. Specifically kynurenic acid (hydrate), quinoline-2-carboxylic acid, quinoline-4-carboxylic acid, quinoline-3-carboxylic acid, and 1,2-dihydro-2-oxo-4-quinoline carboxylic acids possessed the most remarkable growth inhibition capacities against mammary MCF7 cell line, while quinoline-2-carboxylic acid was the only quinoline derivative with significant cytotoxicity on cervical HELA cancer cells. It is highly speculated that chelation with divalent metals via co-planarity with close proximity of the COOH and the N atom could have the potential molecular mechanism for optimally promising repurposed pharmacologies. Conclusively, this study revealed the considerably profound repurposed duality of cytotoxicity and anti-inflammation pharmacologies of quinoline derivatives. Activity-guided structural modifications of the present nuclear scaffolds can be inherently linked to the betterment and enhancement of their repurposed pharmacologies.

Studi Molecular Docking dan Evaluasi Farmakokinetik Senyawa Analog Pirazol Turunan Benzen-Sulfonilurea sebagai Inhibitor Enzim Aldose Reduktase and α-Glukosidase Menggunakan Pendekatan In Silico

The pyrazole scaffold modification in various chemical structures on several studies has shown various biopharmacological activities. This study aims to predict the potential inhibition of pyrazole analogs derived benzene-sulfonylurea (4A, 4B, 4E, 5A, 5C, 5D) against the α-glucosidase (3A4A) and aldose reductase (3RX2) enzymes based on a molecular docking approach using Molecular Operating Environment (MOE) 2020.0102 software and evaluate pharmacokinetic profile (ADMET). In this study, the six test compounds were obtained from previous studies that have been proven antihyperglycemic. The results showed that all the 3,5-disubstituted benzene-sulfonylurea derivative pyrazole analogs are predicted to have low inhibitory activity against the α-glucosidase enzyme. Further, all compounds showed good aldose reductase inhibitor activity and had lower binding free energy values ​​than tolrestat as the positive control (-6.82 kcal/mol). Compound 5C has the best potential inhibitory activity against the aldose reductase enzyme compared to the other test compounds, because it has the lowest binding free energy value (-8.76 kcal/mol) and interacts with important residues on the receptor forming four hydrogen bonds, namely the carbonyl group of SO2 with residues Trp111 and His110, and the carbonyl group of the amide with residues His110 and Tyr48, as well as 3 hydrophobic bonds, namely a pyrazole ring with residues Leu300, Trp219 and a furan ring with Phe122. ADMET properties of the compounds are also predicted. This information provides an opportunity for a 5C compound as an aldose reductase inhibitor agent to develop drug candidates with better and safer activities.

RGD-functionalised self-assembling peptide hydrogel induces a proliferative profile in human osteoblasts in vitro.

Self-assembling peptide hydrogels (SAPHs) have been used in the past decade as reliable three-dimensional (3D) synthetic scaffolds for the culture of a variety of mammalian cells in vitro. Thanks to their versatile physicochemical properties, they allow researchers to tailor the hydrogel properties, including stiffness and functionality to the targeted cells and cells' behaviour. One of the advantages of using SAPH scaffolds is the ease of functionalisation. In the present work, we discuss the effect that functionalising the FEFEFKFK (F, phenylalanine; K, lysine; and E, glutamic acid) hydrogel scaffold using the cell-binding RGDS (fibronectin - R, arginine; G, glycine; D, aspartic acid; S, serine) epitope affects the material properties as well as the function of encapsulated human osteoblast cells. RGDS functionalisation resulted in cells adopting an elongated morphology, suggesting attachment and increased proliferation. While this led to higher cell viability, it also resulted in a decrease in extra-cellular matrix (ECM) protein production as well as a decrease in calcium ion deposition, suggesting lower mineralisation capabilities. The work clearly shows that SAPHs are a flexible platform that allow the modification of scaffolds in a controlled manner to investigate cell-material interactions.

Copper(0)-Catalyzed Reductive Coupling of Disulfurating Reagents and (Hetero)aryl/Alkyl Halides.

Herein, we reported a copper(0)-catalyzed reductive coupling of disulfurating reagents and (hetero)aryl/alkyl halides. Copper(0) can be directly inserted into tetrasulfide and then undergoes reductive coupling with (hetero)aryl Iodides to construct disulfide. The method features the unprecedented use of copper(0)-catalyzed disulfurating reagents (tetrasulfides) in cross-coupling chemistry and is convenient with broad substrate scopes, even applicable to different halogenated hydrocarbons. It is worth noting that the methodology is practical with the late-stage modification of bioactive scaffolds of pharmaceuticals. In the meantime, the synthesis of disulfides is successfully achieved on a gram scale, indicating the approach is highly valuable.

Palladium-Catalyzed Hiyama-Type Coupling of Thianthrenium and Phenoxathiinium Salts.

Here, we demonstrate palladium-catalyzed Hiyama-type cross-coupling reactions of aryl thianthrenium or phenoxathiinium salts. By employing stable and inexpensive organosilanes, the arylation, alkenylation, and alkynylation were realized in high efficiency using commercially available Pd(tBu3P)2 as the catalyst, thus providing a reliable method for preparation of biaryls, styrenes, and aryl acetylenes with a broad functional group tolerance under mild conditions. Given the accessibility of aryl thianthrenium or phenoxathiinium salts from simple arenes in a remarkable regioselective fashion, this protocol also provides an attractive approach for the late-stage modification of complex bioactive scaffolds.

Regioselective Deacetylation in Nucleosides and Derivatives.

Nucleoside analogues are a promising class of natural compounds in the pharmaceutical industry, and many antiviral, antibacterial and anticancer drugs have been created through structural modification of nucleosides scaffold. Acyl protecting groups, especially the acetyl group, play an important role in the protection of hydroxy groups in nucleoside synthesis and modification; consequently, numerous methodologies have been put forth for the acetylation of free nucleosides. However, for nucleosides that contain different O- and N-based functionalities, selective deprotection of the acetyl group(s) in nucleosides has been studied little, despite its practical significance in simplifying the preparation of partially or differentially substituted nucleoside intermediates. In this mini-review, recent approaches for regioselective deacetylation in acetylated nucleosides and their analogues are summarized and evaluated. Different regioselectivities (primary ester, secondary ester, full de-O-acetylation, and de-N-acetylation) are summarized and discussed in each section.

Silver phosphate-modified carbonate apatite honeycomb scaffolds for anti-infective and pigmentation-free bone tissue engineering

Bone regeneration using synthetic materials has a high rate of surgical site infection, resulting in severe pain for patients and often requiring revision surgery. We propose Ag3PO4-based surface modification and structural control of scaffolds for preventing infections in bone regeneration. We demonstrated the differences in toxicity and antibacterial activity between in vitro and in vivo studies and determined the optimal silver content in terms of overall anti-infection effects, bone regeneration, toxicity, and pigmentation. A honeycomb structure comprising osteoconductive and resorbable carbonate apatite (CAp) was used as the base scaffold. CAp in the scaffold surface was partially replaced with different concentrations of Ag3PO4 via controlled dissolution-precipitation reactions in an AgNO3 solution. Both bone regeneration and infection prevention were achieved at 860–2300 ppm of silver. Despite the absence of Ag3PO4, honeycomb scaffolds were less susceptible to infection, even under conditions where infection occurs in clinically used three-dimensional porous scaffolds. Regardless of in vitro cytotoxicity at >5200 ppm of silver, increasing the silver content to 21,000 ppm did not adversely affect in vivo bone formation and scaffold resorption or cause acute systemic toxicity. Rather, bone formation was enhanced with 5200 ppm of silver. However, pigmentation was observed at that concentration. Hence, we concluded that the optimal silver concentration range is 860–2300 ppm for anti-infective and pigmentation-free bone regeneration. Bone regeneration was achieved via surface modification, resulting in the rapid release of silver ions immediately after implantation, followed by gradual release over several months. The scaffold structure may also aid in preventing bacterial growth within the scaffolds.

3D Printing and Surface Engineering of Ti6Al4V Scaffolds for Enhanced Osseointegration in an In Vitro Study.

Ti6Al4V superalloy is recognized as a good candidate for bone implants owing to its biocompatibility, corrosion resistance, and high strength-to-weight ratio. While dense metal implants are associated with stress shielding issues due to the difference in densities, stiffness, and modulus of elasticity compared to bone tissues, the surface of the implant/scaffold should mimic the properties of the bone of interest to assure a good integration with a strong interface. In this study, we investigated the additive manufacturing of porous Ti6Al4V scaffolds and coating modification for enhanced osteoconduction using osteoblast cells. The results showed the successful fabrication of porous Ti6Al4V scaffolds with adequate strength. Additionally, the surface treatment with NaOH and Dopamine Hydrochloride (DOPA) promoted the formation of Dopamine Hydrochloride (DOPA) coating with an optimized coating process, providing an environment that supports higher cell viability and growth compared to the uncoated Ti6Al4V scaffolds, as demonstrated by the higher proliferation ratios observed from day 1 to day 29. These findings bring valuable insights into the surface modification of 3D-printed scaffolds for improved osteoconduction through the coating process in solutions.

Computational Design of Bidentate Hypervalent Iodine Catalysts in Halogen Bond-Mediated Organocatalysis.

In recent years, halogen bond-based organocatalysis has garnered significant attention as an alternative to hydrogen-based catalysis, capturing considerable interest within the scientific community. This transition has witnessed the evolution of catalytic scaffolds from monodentate to bidentate architectures, and from monovalent to hypervalent species. In this DFT-based study, we explored a bidentate hypervalent iodine(III)-based system that has already undergone experimental validation. Additionally, we explore various functionalisations (-CF3, -CH3, -tBu, -OH, -OMe, -NO2, -CN) and scaffold modifications, such as sulfur oxidation, theoretically proposed for an indole-based Michael addition. The investigated systems favour bidentate O-type binding, underlining the importance of ligand coordination in catalytic activity. Electron-deficient scaffolds exhibited stronger binding and lower activation energies, indicating the pivotal role of electronic properties for σ-hole-based catalysis. Of these groups, Lewis-base-like moieties formed stabilising intramolecular interactions with hypervalent iodines when in the ortho-position. Furthermore, inductive electron withdrawal was deemed more effective than mesomeric withdrawal in enhancing catalytic efficacy for these systems. Lastly, increasing sulfur oxidation was theoretically proven to improve catalytic activity significantly.

Dual-layered carbonated hydroxyapatite/polypyrrole: A novel strategy for bone fracture repair implants

This study presents the fabrication of a carbonate-doped hydroxyapatite/polypyrrole thin film on 304 stainless steel (CHA/PPY/304 SS) using a cyclic voltammetry electrochemical method to enhance bone fracture repair. The in-situ substitution mechanism was evaluated through estimated reaction energy, and the impact of surface modification on structural properties was examined using the Rietveld refinement method. Following the electrodeposition of CHA on PPY-coated 304 SS, a distinctive flower-like structure emerged, with average cluster and pore sizes of 3 ± 1 μm and 130 ± 10 nm, respectively. Rietveld refinement analysis revealed A-type carbonate substitution, indicated by an increase in the a parameter and a reduction in the c parameter compared to the standard. Subsequent deposition of the bilayer coating on 304 SS significantly improved adhesion strength to 10.7 ± 0.2 MPa, along with increased hydrophilicity and Vickers hardness. Notably, enhanced bioactivity was observed, evidenced by thickened nanoflake-like structures and the formation of island-like apatite deposits after immersion in simulated body fluid (SBF) for 7 days. This bilayer coating shows promise for surface modification of metallic implants and tissue engineering scaffolds.

Influence of Hydroxyapatite Content on Physical and Rheological Properties of Chitosan-based Scaffold

Chitosan-based scaffolds offer significant potential in tissue engineering and regenerative medicine. Whilst exhibiting great bio-regenerative and biocompatible properties, their mechanical properties remain quite poor. The presented research is focused on the modification of macroporous chitosan scaffolds with various amounts of bioactive ceramics (hydroxyapatite) and its influence on the physical and rheological properties of the composite scaffold. Chitosan/hydroxyapatite composite scaffolds with a highly porous microstructure have been prepared by suspending hydroxyapatite (HAp) particles into the chitosan matrix. According to SEM imaging, homogeneous dispersion of the inorganic phase in a chemically-crosslinked chitosan matrix had been achieved. The obtained composite scaffolds exhibited lower swelling capacity with respect to pure chitosan after 24 h of incubation in Hanks’ balanced salt solution. Rheological measurements show an increase in storage and loss modulus indicating an improvement in mechanical properties under shear stress. Furthermore, no significant change in loss factor (tanδ) was observed indicating no change in composite viscoelastic properties with an increase in HAp content.

Tuning the Thermochemistry and Reactivity of a Series of Cu-Based 4H+/4e- Electron-Coupled-Proton Buffers.

Electron-coupled-proton buffers (ECPBs) store and deliver protons and electrons in a reversible fashion. We have recently reported an ECPB based on Cu and a redox-active ligand that promoted 4H+/4e- reversible transformations (J. Am. Chem. Soc. 2022, 144, 16905). Herein, we report a series of Cu-based ECPBs in which the ability of these to accept and/or donate H• equivalents can be tuned via ligand modification. The thermochemistry of the 4H+/4e- ECPB equilibrium was determined using open-circuit potential measurements. The reactivity of the ECPBs against proton-coupled electron transfer (PCET) reagents was also analyzed, and the results obtained were rationalized based on the thermochemical parameters. Experimental and computational analysis of the thermochemistry of the H+/e- transfers involved in the 4H+/4e- ECPB transformations found substantial differences between the stepwise (namely, BDFE1, BDFE2, BDFE3, and BDFE4) and average bond dissociation free energy values (BDFEavg.). Our analysis suggests that this "redox unleveling" is critical to promoting the disproportionation and ligand-exchange reactions involved in the 4H+/4e- ECPB equilibria. The difference in BDFEavg. within the series of Cu-based ECPBs was found to arise from a substantial change in the redox potential (E1/2) upon modification of the ligand scaffold, which is not fully compensated for by a change in the acidity/basicity (pKa), suggesting "thermochemical decompensation".

Room Temperature Phosphorescence in Crystalline Iodinated Eumelanin Monomer.

We report the room temperature phosphorescence upon iodination on a crystalline eumelanin monomer with shielded hydroxyl moieties, ethyl 5,6-dimethoxyindole-2-carboxylate (DMICE). Ultrafast intersystem crossing (ISC) is observed in the iodinated (IDMICE) as well as brominated (BDMICE) analogues of the eumelanin monomer derivative in solution. The triplet quantum yields (φT) and intersystem crossing rates (kISC) of the halogenated eumelanin derivatives are =25.4±1.1 %; =1.95×109 s-1 and =59.1±1.6 %; 1.36×1010 s-1, as monitored using transient absorption spectroscopy. Theoretical calculations based on nuclear ensemble method reveal that computed kISC and spin-orbit coupling matrix elements for eumelanin derivatives are larger for IDMICE relative to BDMICE. The halogen and π-π interactions, with distinct excitonic coupling and higher ISC rate promote phosphorescence in IDMICE molecular crystals. Accessing triplet excited states and resultant photoluminescence through structural modification of eumelanin scaffolds paves way for exploring the versatility of eumelanin-inspired molecules as bio-functional materials.

The Advent of Bodipy-based Chemosensors for Sensing Fluoride Ions: A Literature Review.

The detection of fluoride ions in water and other sources is crucial because they can harm human health if they exceed the safe limit of 1-1.5 ppm. BODIPY (boron dipyrromethene) dyes are promising fluorophores for chemosensors, and their design and modification have attracted a lot of attention. Their advantages include visible light excitation and emission, high molar absorption coefficients (ε) and fluorescence quantum yields [ϕ (λ)], and flexible scaffold manipulation for various applications. In this article, we review the progress of BODIPY-based sensors for fluoride ions from the early 2000s to the present. We focus on the different scaffold modifications of the sensors and their corresponding responses, as well as the underlying photophysical mechanisms and potential uses of each sensor.

Abstract 4487: Simple modifications of 3-HPT for improved in-vivo activtiy

Abstract One of the key targets in the treatment of castration resistant prostate cancer is HDAC6. HDAC6 removes acetyl groups from Heat shock protein 90 (HSP90), which is a protein chaperone that folds the androgen receptor. By inhibiting HDAC6 it is possible to prevent the expression of mutated androgen receptors, that are no longer responsive to androgen deprivation therapy, treating castration resistant prostate cancer. The Oyelere lab has previously demonstrated that 3-Hydroxypyridin-2-thione (3-HPT) can serve as a scaffold for HDAC6 inhibitors. While the unaltered 3-HPT has been shown on its own to inhibit HDAC6 in enzyme specific assays. The unaltered 3-HPT had no effect in whole cell assays. This work investigated simple modification of the 3-HPT scaffold to improve the in-vivo activity of 3-HPT. This work is an extension of work previously done in the Oyelere lab. The aim of this work is to apply simple modifications to the 3-HPT scaffold to improve the in-vitro activity. Previously 3-HPT was shown on its own to inhibit HDAC6 with an IC50 of 681nM but have no effect on cell assays. The hypothesis was that by converting the secondary amine into a tertiary amine the pharmacokinetic-properties of 3-HPT allowing can be improved focusing on cellular entry. The specific modification was the addition of alkanes and fluorinated alkanes at the secondary amine. This addition should improve the charge of the compounds improving the invitro activity. Based on molecular docking studies using Autodock vina, the introduction of fluorines improves the binding to HDAC6 by interacting with a hydrophilic pocket near the zinc ion. The preliminary in-vivo results in LnCAP and DU145 cells demonstrate that the addition of fluorinated alkanes has substantially improved the IC50 compared to the base 3-HPT compound. The base 3-HPT compound has an IC50 of greater than 100µM while the compounds with fluorinated alkanes have IC50 values in the range of 2-15µM. this data indicates improved drug likeness. Preliminary IC50 values of compounds in prostate cancer cell lines Compound Name LNCaPIC50 (µM) DU145IC50 (µM) Vero IC50 (µM) SH-1-78 >100 >100 >100 SH-1-94 2.50 19.29 22.53 RK-1-187 96.95 95.45 88.57 SH-1-110 1.27 21.47 17.41 RK-2-16 2.09 62.86 18.76 RK-2-17 >100 >100 >100 RK-2-64 78.36 >100 76.45 RK-2-67 14.19 26.95 11.38 Citation Format: Ryan E. Kern, Susanna Huang, Uche Arunsi, Adegboyega Oyelere. Simple modifications of 3-HPT for improved in-vivo activtiy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4487.

Discovery of Conformationally Constrained ALK2 Inhibitors.

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors M4K2308 and M4K2281 and the amine-linked inhibitors M4K2304 and M4K2306, each with superior potency against ALK2. Notably, M4K2304 and M4K2306 exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG.

Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks.

Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence PARP1 allostery in addition to preventing catalytic activity. Using the benzimidazole-4-carboxamide pharmacophore present in the first generation PARP1 inhibitor veliparib, a series of 11 derivatives was designed, synthesized, and evaluated as allosteric PARP1 inhibitors, with the premise that bulky substituents would engage the regulatory helical domain (HD) and thereby promote PARP1 retention on DNA breaks. We found that core scaffold modifications could indeed increase PARP1 affinity for DNA; however, the bulk of the modification alone was insufficient to trigger PARP1 allosteric retention on DNA breaks. Rather, compounds eliciting PARP1 retention on DNA breaks were found to be rigidly held in a position that interferes with a specific region of the HD domain, a region that is not targeted by current clinical PARP inhibitors. Collectively, these compounds highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties.