Synthesis and Pharmacological Evaluation of Enantiopure N-Substituted Ortho-c Oxide-Bridged 5-Phenylmorphans.

The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM).

Hydrochloride Salt of the GABAkine KRM-II-81.

Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABAA receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1H NMR and 13C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation.

Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines.

In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), and 1 Amido-DihydroMorHap epimer (4). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)-hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT-hapten conjugates induced high antibody endpoint titers against the targets but only haptens 2 and 3 can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, 1 and 4, failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT-2 and TT-3 yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT-hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT-3 interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness.

Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy.

We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (±)-9 vs threo, (±)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9 enantiomers, (-)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein- vs ß-arrestin1/2-dependent signaling. (-)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.

Reply to the 'Comment on "Investigation of Zr(iv) and 89Zr(iv) complexation with hydroxamates: progress towards designing a better chelator than desferrioxamine B for immuno-PET imaging"' by A. Bianchi and M. Savastano, Chem. Commun., 2020, 56, D0CC01189D.

The alternative analysis of A. Bianchi and M. Savastano is a valuable contribution to the understanding of the complex systems at stake in the complexation chemistry of Zr4+ by considering polynuclear species. Placed in the context of nuclear medicine where such aggregates are unlikely and considering recent literature data, this however points out that no clear agreement exists to describe such complex formation.

X-ray Crystallography and Unexpected Chiroptical Properties Reassign the Configuration of Haliclonadiamine.

Haliclonadiamine and papuamine are bis-indane marine natural products isolated from the marine sponge Haliclona sp. Their relative structures were previously reported to differ by inversion at only one of their eight shared stereocenters. Here X-ray crystallography shows the opposite to be true: papuamine has a 1R,3S,8R,9S,14S,15R,20S,22R configuration, while haliclonadiamine has a 1S,3R,8S,9R,14R,15S,20R,22R configuration. Paradoxically the ECD of each structure displays a negative Cotton effect. X-ray crystallography reveals the two structures adopt similar conformations of their 13-membered macrocyclic core that comprises a configurationally relevant diene. B97x-D/Def2-TZVPP-(MeOH)-calculated ECD supports the diene configuration with the macrocycle dominating the ECD Cotton effect for haliclonadiamine and papuamine. Additional crystallographic and chiroptical analyses of three sponge samples from geographically distant locations indicate this pair of natural products always exists as a configurationally related couple. The co-discovery of a biosynthetic precursor, halichondriamine C, present in these same Haliclona samples must be considered when discussing any biosynthetic pathway. Taken together, this work justifies a reassignment of haliclonadiamine's structure and opens the question of how this complex stereochemical relationship between haliclonadiamine and palauamine arises biosynthetically.

G-Protein biased opioid agonists: 3-hydroxy-N-phenethyl-5-phenylmorphans with three-carbon chain substituents at C9.

A series of compounds have been synthesized with a variety of substituents based on a three-carbon chain at the C9-position of 3-hydroxy-N-phenethyl-5-phenylmorphan (3-(2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol). Three of these were found to be µ-opioid receptor agonists in the inhibition of forskolin-induced cAMP accumulation assay and they did not recruit ß-arrestin at all in the PathHunter assay and in the Tango assay. Compound 12 (3-((1S,5R,9R)-2-phenethyl-9-propyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), 13 (3-((1S,5R,9R)-9-((E)-3-hydroxyprop-1-en-1-yl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), and 15a (3-((1S,5R,9R)-9-(2-hydroxypropyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol) were partial µ-agonists. Two of them had moderate efficacies (E MAX ca. 65%) and one had lower efficacy, and they were ca. 5, 3, and 4 times more potent, respectively, than morphine in vitro. Computer simulations were carried out to provide a molecular basis for the high bias ratios of the C9-substituted 5-phenylmorphans toward G-protein activation.

A Novel Bromine-Containing Paroxetine Analogue Provides Mechanistic Clues for Binding Ambiguity at the Central Primary Binding Site of the Serotonin Transporter.

The serotonin transporter (SERT) is the primary target for the selective serotonin reuptake inhibitors (SSRIs). However, the structural basis for the extraordinarily high binding affinity of the widely prescribed SSRI, paroxetine, to human SERT (hSERT) has not yet been fully elucidated. Our previous findings unveiled a plausible ambiguity in paroxetine's binding orientations that may constitute an integral component of this SSRI's high affinity for hSERT. Herein, we investigate factors contributing to paroxetine's high affinity by modifying both the ligand and the protein. We generated a series of bromine (Br)-containing derivatives and found that the one in which the 4-F of paroxetine had been replaced with the chemically similar but more electron-rich Br atom (13) had the highest affinity. By comparatively characterizing the binding of paroxetine and 13 to both wild type (WT) and a construct harboring a paroxetine-sensitive mutation in the binding cavity, we identified a mechanistic determinant responsible for the pose ambiguity of paroxetine, which can guide future drug design.

Synthesis and Characterization of the Selective, Reversible PKCß Inhibitor (9 S)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, Ruboxistaurin (LY333531).

The demonstrated role of PKCß in  mediating amphetamine-stimulated dopamine efflux, which regulates amphetamine-induced dopamine transporter trafficking and activity, has promoted the research use of the selective, reversible PKCß inhibitor (9 S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, ruboxistaurin. Despite the interest in development of ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization of ruboxistaurin free base (as a monohydrate), including X-ray crystallography to confirm the absolute configuration, and of the mesylate salt, isolated as a hydrate containing 1.5 mol of water per mole.

Conformational Details of Quantum Dot-DNA Resolved by Förster Resonance Energy Transfer Lifetime Nanoruler.

DNA-nanoparticle conjugates are important tools in nanobiotechnology. Knowing the orientation, function, and length of DNA on nanoparticle surfaces at low nanomolar concentrations under physiological conditions is therefore of great interest. Here, we investigate the conformation of a 31 nucleotides (nt) long DNA attached to a semiconductor quantum dot (QD) via Förster resonance energy transfer (FRET) from Tb-DNA probes hybridized to different positions on the QD-DNA. Precise Tb-to-QD distance determination from 7 to 14 nm along 26 nt of the peptide-appended QD-DNA was realized by time-resolved FRET spectroscopy. The FRET nanoruler measured linear single-stranded (ssDNA) and double-stranded (dsDNA) extensions of ∼0.15 and ∼0.31 nm per base, reflecting the different conformations. Comparison with biomolecular modeling confirmed the denser conformation of ssDNA and a possibly more flexible orientation on the QD surface, whereas the dsDNA was fully extended with radial orientation. The temporally distinct photoluminescence decays of the different DNA-FRET configurations were used for prototypical DNA hybridization assays that demonstrated the large potential for extended temporal multiplexing. The extensive experimental and theoretical analysis of 11 different distances/configurations of the same QD-DNA conjugate provided important information on DNA conformation on nanoparticle surfaces and will be an important benchmark for the development and optimization of DNA-nanobiosensors.

B-973, a Novel α7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation.

We report here the total synthesis of B-973 (five steps), a recently identified α7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X-ray crystallography studies revealed its absolute "S" stereochemistry. B-973B was effective in attenuating pain behavior and decreasing paw edema (formalin test), and its analgesic effects were mediated through α7 nAChR.

A High Aspect Ratio Bifurcated 128-Microchannel Microfluidic Device for Environmental Monitoring of Explosives.

Design and evolution of explosives monitoring and detection platforms to address the challenges of trace level chemical identification have led investigations into the use of intricately designed microfluidic devices. Microfluidic devices are unique tools that possess distinct characteristics that, when designed properly and configured with optical and fluidic components, can produce detection platforms with unmatched performance levels. Herein, we report the design, fabrication and integration of a bifurcated high aspect ratio microfluidic device containing 128 microchannels (40 mm × 40 µm × 250 µm; L × W × H) for explosives detection at trace levels. Aspect ratios measuring >6:1 support improved receptor-target molecule interactions, higher throughput and extremely low limits of detection (LOD). In addition to superior assay sensitivity, the bifurcated microfluidic device provides greater durability and versatility for substrate modification. Using the explosive 2,4,6-trinitrotoluene (TNT) as the model compound in a fluorescence-based displacement immunoassay, we report LODs for TNT at 10 parts-per-trillion (pptr) using a neutravidin-coated biotinylated anti-TNT microfluidic device. Solution to wall interactions were also simulated in COMSOL Multiphysics to understand fluid flow characteristics. Reynolds numbers were calculated to be 0.27⁻2.45 with a maximum pressure of 1.2 × 10-2 psi.

Synthesis and Structural Elucidation of a Pyranomorphinan Opioid and in Vitro Studies.

During optimization of the synthesis of the mixed µ opioid agonist/δ opioid antagonist 5-(hydroxymethyl)oxymorphone (UMB425) for scale-up, it was unexpectedly discovered that the 4,5-epoxy bridge underwent rearrangement on treatment with boron tribromide (BBr3) to yield a novel opioid with a little-studied pyranomorphinan skeleton. This finding opens the pyranomorphinans for further investigations of their pharmacological profiles and represents a novel drug class with the dual profile (µ vs δ) predicted to yield lower tolerance and dependence. The structure was assigned with the help of 1D, 2D NMR and the X-ray crystal structure.

Two CuII complexes of 3,4,5-tri-methyl-1H-pyrazole.

The crystal structure of complexes of 3,4,5-tri-methyl-1H-pyrazole with CuCl2·2H2O and Cu(NO3)2·2.5H2O are presented, namely di-µ-chlorido-bis[chloridobis(3,4,5-trimethyl-1H-pyrazole-κN2)copper(II)], [Cu2Cl4(C6H10N2)4] (1) and aquatetrakis(3,4,5-trimethyl-1H-pyrazole-κN2)copper(II) dinitrate, [Cu(C6H10N2)4(H2O)](NO3)2 (2), and compared to the previously determined structures for 3-methyl-1H-pyrazole and 3,5-di-methyl-1H-pyrazole. CuCl2 forms a 2:1 ligand-to-metal chloride-bridged complex with 3,4,5-tri-methyl-1H-pyrazole, with a square-pyramidal coordination geometry about each copper(II) center. Similarly to the previously obtained 3,5-di-methyl-1H-pyrazole complex with CuCl2, the pyrazole ligands are cis to each other, with two chloride ions bridging the two copper(II) centers, and a terminal chloride ion occupying the axial position. Cu(NO3)2 forms a 4:1 ligand-to-metal complex with 3,4,5-tri-methyl-1H-pyrazole that is also arranged in a square-pyramidal geometry about CuII. The newly obtained copper(II) complex has the same coordination geometry as the 3,5-di-methyl-1H-pyrazole complex, including an axial water mol-ecule, two nitrate ions hydrogen-bonded to the water mol-ecule, and four pyrazole ligands in the equatorial plane, suggesting that similar steric forces are at play in the formation of these complexes.

Reaction Kinetics Direct a Rational Synthesis of an HIV-1 Inactivator of Nucleocapsid Protein 7 and Provide Mechanistic Insight into Cellular Metabolism and Antiviral Activity.

Mercaptobenzamide thioester SAMT-247 is a non-toxic, mutation-resistant HIV-1 maturation inhibitor with a unique mechanism of antiviral activity. NMR spectroscopic analyses of model reactions that mimic the cellular environment answered fundamental questions about the antiviral mechanism and inspired a high-yielding (64 % overall), scalable (75 mmol), and cost-effective ($4 mmol-1 ) three-step synthesis that will enable additional preclinical evaluation.

A Stable Heroin Analogue That Can Serve as a Vaccine Hapten to Induce Antibodies That Block the Effects of Heroin and Its Metabolites in Rodents and That Cross-React Immunologically with Related Drugs of Abuse.

An improved synthesis of a haptenic heroin surrogate 1 (6-AmHap) is reported. The intermediate needed for the preparation of 1 was described in the route in the synthesis of 2 (DiAmHap). A scalable procedure was developed to install the C-3 amido group. Using the Boc protectng group in 18 allowed preparation of 1 in an overall yield of 53% from 4 and eliminated the necessity of preparing the diamide 13. Hapten 1 was conjugated to tetanus toxoid and mixed with liposomes containing monophosphoryl lipid A as an adjuvant. The 1 vaccine induced high anti-1 IgG levels that reduced heroin-induced antinociception and locomotive behavioral changes following repeated subcutaneous and intravenous heroin challenges in mice and rats. Vaccinated mice had reduced heroin-induced hyperlocomotion following a 50 mg/kg heroin challenge. The 1 vaccine-induced antibodies bound to heroin and other abused opioids, including hydrocodone, oxycodone, hydromorphone, oxymorphone, and codeine.

Total Synthesis of Sarpagine-Related Bioactive Indole Alkaloids.

Extension of the asymmetric Pictet-Spengler reaction to bulkier Nb -alkylated tryptophan derivatives resulted in an improved stereospecific access to the key bicyclo[3.3.1]nonane core of bioactive C-19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids with excellent diastereoselectivity by internal asymmetric induction. Complete stereocontrol of the C-19 methyl function in either the α- or ß-configuration was achieved, which enables the total synthesis of any member from this group of thirty alkaloids. We report herein, the total synthesis of macrocarpines (A-C) 1-3, talcarpine 4, N(4)-methyl-N(4),21-secotalpinine 5, dihydroperaksine 8 and deoxyperaksine 9.

Concise Total Synthesis of (-)-Affinisine Oxindole, (+)-Isoalstonisine, (+)-Alstofoline, (-)-Macrogentine, (+)-Na -Demethylalstonisine, (-)-Alstonoxine†A, and (+)-Alstonisine.

A highly enantio- and diastereoselective strategy to access any member of the sarpagine/macroline family of oxindole alkaloids via internal asymmetric induction was developed from readily available d-(+)-tryptophan. At the center of this approach was the diastereospecific generation of the spiro[pyrrolidine-3,3'-oxindole] moiety at an early stage via a tert-butyl hypochlorite-promoted oxidative rearrangement of a chiral tetrahydro-ß-carboline derivative. This key branching point determined the spatial configuration at the C-7 spiro center to be entirely 7R or 7S. Other key stereospecific processes were the asymmetric Pictet-Spengler reaction and Dieckmann cyclization, which were scalable to the 600 and 150 gram levels, respectively. Execution of this approach resulted in first enantiospecific total synthesis of (+)-isoalstonisine and (-)-macrogentine from the chitosenine series (7R), as well as (+)-alstonisine, (+)-alstofoline, (-)-alstonoxine A and (+)-Na -demethylalstonisine from the alstonisine series (7S).

Crystal structures of the three closely related compounds: bis-[(1H-tetra-zol-5-yl)meth-yl]nitramide, tri-amino-guanidinium 5-({[(1H-tetra-zol-5-yl)meth-yl](nitro)-amino}-meth-yl)tetra-zol-1-ide, and di-ammonium bis-[(tetra-zol-1-id-5-yl)meth-yl]nitramide monohydrate.

In the mol-ecule of neutral bis-[(1H-tetra-zol-5-yl)meth-yl]nitramide, (I), C4H6N10O2, there are two intra-molecular N-H⋯O hydrogen bonds. In the crystal, N-H⋯N hydrogen bonds link mol-ecules, forming a two-dimensional network parallel to (-201) and weak C-H⋯O, C-H⋯N hydrogen bonds, and inter-molecular π-π stacking completes the three-dimensional network. The anion in the molecular salt, tri-amino-guanidinium 5-({[(1H-tetra-zol-5-yl)meth-yl](nitro)-amino}-meth-yl)tetra-zol-1-ide, (II), CH9N6+·C4H5N10O2-, displays intra-molecular π-π stacking and in the crystal, N-H⋯N and N-H⋯O hydrogen bonds link the components of the structure, forming a three-dimensional network. In the crystal of di-ammonium bis-[(tetra-zol-1-id-5-yl)meth-yl]nitramide monohydrate, (III), 2NH4+·C4H4N10O22-·H2O, O-H⋯N, N-H⋯N, and N-H⋯O hydrogen bonds link the components of the structure into a three-dimensional network. In addition, there is inter-molecular π-π stacking. In all three structures, the central N atom of the nitramide is mainly sp2-hybridized. Bond lengths indicate delocalization of charges on the tetra-zole rings for all three compounds. Compound (II) was found to be a non-merohedral twin and was solved and refined in the major component.

Nanoparticle cellular uptake by dendritic wedge peptides: achieving single peptide facilitated delivery.

Significant efforts are being undertaken to optimize the cargo carrying capacity and especially the cellular delivery efficiency of functionalized nanoparticles for applications in biological research and pharmacological delivery. One approach to increasing nanoparticle surface cargo display capacity is to decrease the number of moieties required for mediating cellular delivery by improving their efficiency. We describe a series of multivalent cell penetrating peptide (CPP) dendrimers that facilitate rapid cellular delivery of prototypical nanoparticle-semiconductor quantum dots (QDs). The modular CPP dendrimers were assembled through an innovative convergent oxime ligation strategy between (Arg9)n motifs and a dendritic QD-coordination scaffold. Dendrimeric peptides sequentially incorporate a terminal (His)6 motif for metal-affinity QD coordination, a Pro9 spacer, a branching poly-lysine scaffold, and wedged display of (Arg9)n binding motifs with n = 1×, 2×, 4×, 8×, 16× multivalency. QD dendrimer display capacity was estimated using structural simulations and QD-(Arg9)1-16 conjugates characterized by dynamic light scattering along with surface plasmon resonance-based binding assays to heparan sulfate proteoglycan surfaces. Cellular uptake via endocytosis was confirmed and peptide delivery kinetics investigated as a function of QD-(Arg9)1-16 conjugate exposure time and QD assembly ratio where cellular viability assays reflected no overt cytotoxicity. The ability of single dendrimer conjugates to facilitate cellular uptake was confirmed for QD-(Arg9)2-16 repeats along with the ability to deliver >850 kDa of protein cargo per QD. Minimizing the number of CPPs required for cellular uptake is critical for expanding nanoparticle cargo carrying capacity and can allow for inclusion of additional sensors, therapeutics and contrast agents on their surface.