Targeting DNA mismatches with rhodium metalloinsertors

DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells. Here, we review a family of complexes, termed rhodium metalloinsertors, that selectively target DNA base pair mismatches, a hallmark of mismatch repair (MMR)-deficient cancers. These rhodium metalloinsertors bind DNA mismatches with high specificity and display high selectively in killing MMR-deficient versus MMR-proficient cells. This cell selectivity is unique among small molecules that bind DNA. Current generations of rhodium metalloinsertors have shown nanomolar potency along with high selectivity towards MMR-deficient cells, and show promise as a foundation for a new family of chemotherapeutics for MMR-deficient cancers

A Family of Rhodium Complexes with Selective Toxicity towards Mismatch Repair-Deficient Cancers

Rhodium metalloinsertors are a unique set of metal complexes that bind specifically to DNA base pair mismatches in vitro and kill mismatch repair (MMR)-deficient cells at lower concentrations than their MMR-proficient counterparts. A family of metalloinsertors containing rhodium–oxygen ligand coordination, termed “Rh–O” metalloinsertors, has been prepared and shown to have a significant increase in both overall potency and selectivity toward MMR-deficient cells regardless of structural changes in the ancillary ligands. Here we describe DNA-binding and cellular studies with the second generation of Rh–O metalloinsertors in which an ancillary ligand is varied in both steric bulk and lipophilicity. These complexes, of the form [Rh(L)(chrysi)(PPO)]^(2+), all include the O-containing PPO ligand (PPO = 2-(pyridine-2-yl)propan-2-ol) and the aromatic inserting ligand chrysi (5,6-chrysene quinone diimine) but differ in the identity of their ancillary ligand L, where L is a phenanthroline or bipyridyl derivative. The Rh–O metalloinsertors in this family all show micromolar binding affinities for a 29-mer DNA hairpin containing a single CC mismatch. The complexes display comparable lipophilic tendencies and pK_a values of 8.1–9.1 for dissociation of an imine proton on the chrysi ligand. In cellular proliferation and cytotoxicity assays with MMR-deficient cells (HCT116O) and MMR-proficient cells (HCT116N), the complexes containing the phenanthroline-derived ligands show highly selective cytotoxic preference for the MMR-deficient cells at nanomolar concentrations. Using mass spectral analyses, it is shown that the complexes are taken into cells through a passive mechanism and exhibit low accumulation in mitochondria, an off-target organelle that, when targeted by parent metalloinsertors, can lead to nonselective cytotoxicity. Overall, these Rh–O metalloinsertors have distinct and improved behavior compared to previous generations of parent metalloinsertors, making them ideal candidates for further therapeutic assessment

Leakage-Resilient Inner-Product Functional Encryption in the Bounded-Retrieval Model

We propose a leakage-resilient inner-product functional encryption scheme (IPFE) in the bounded-retrieval model (BRM). This is the first leakage-resilient functional encryption scheme in the BRM. In our leakage model, an adversary is allowed to obtain at most $l$-bit knowledge from each secret key. And our scheme can flexibly tolerate arbitrarily leakage bound $l$, by only increasing the size of secret keys, while keeping all other parts small and independent of $l$. Technically, we develop a new notion: Inner-product hash proof system (IP-HPS). IP-HPS is a variant of traditional hash proof systems. Its output of decapsulation is an inner-product value, instead of the encapsulated key. We propose an IP-HPS scheme under DDH-assumption. Then we show how to make an IP-HPS scheme to tolerate $l\u27$-bit leakage, and we can achieve arbitrary large $l\u27$ by only increasing the size of secret keys. Finally, we show how to build a leakage-resilient IPFE in the BRM with leakage bound $l=\frac{l\u27}{n}$ from our IP-HPS scheme

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

Synthesis, characterization, and biological activity of DNA mismatch-targeting rhodium complexes

DNA base pair mismatches are a promising target for chemotherapeutic design due to their relative abundance in cancers with mismatch repair (MMR) deficiencies. Rhodium metalloinsertors are a family of metal complexes that can target these mismatches with high selectivity in vitro and in cell culture. Mismatch targeting is directed by an expansive inserting ligand, 5,6-chrysiquinone diimine (chrysi), which is able to displace a thermodynamically destabilized mispair and replace it within the DNA π-stack. Recent studies have led to the development of unique metalloinsertors contg. rhodium-oxygen coordination of an ancillary ligand. This new ligand framework has been assocd. with nanomolar potency and improved selective cytotoxicity towards MMR deficient cells over MMR proficient cells. To gain addnl. insight into the surprising behavior of these complexes, this family has been further expanded through alteration of the remaining ancillary ligand, which has been varied in steric bulk and lipophilicity. This newest family of rhodium metalloinsertors has been synthesized and characterized, and the biol. activity of these complexes, including cytotoxicity and subcellular localization, has been measured. Unlike earlier generations of metalloinsertors, even the most lipophilic complexes in this family do not exhibit excessive off-target mitochondrial localization, allowing them to maintain high selective cytotoxicity towards MMR deficient cells and reduced off-target cytotoxicity in MMR proficient cells. Overall, the biol. activity of metalloinsertors contg. this Rh-O ligand coordination appears to be highly robust regardless of substitution of the ancillary ligands. This ligand framework could serve as an excellent scaffold for future conjugation to cytotoxic or fluorescent payloads for therapeutic or diagnostic use

Synthesis, characterization, and biological activity of DNA mismatch-targeting rhodium complexes

DNA base pair mismatches are a promising target for chemotherapeutic design due to their relative abundance in cancers with mismatch repair (MMR) deficiencies. Rhodium metalloinsertors are a family of metal complexes that can target these mismatches with high selectivity in vitro and in cell culture. Mismatch targeting is directed by an expansive inserting ligand, 5,6-chrysiquinone diimine (chrysi), which is able to displace a thermodynamically destabilized mispair and replace it within the DNA π-stack. Recent studies have led to the development of unique metalloinsertors contg. rhodium-oxygen coordination of an ancillary ligand. This new ligand framework has been assocd. with nanomolar potency and improved selective cytotoxicity towards MMR deficient cells over MMR proficient cells. To gain addnl. insight into the surprising behavior of these complexes, this family has been further expanded through alteration of the remaining ancillary ligand, which has been varied in steric bulk and lipophilicity. This newest family of rhodium metalloinsertors has been synthesized and characterized, and the biol. activity of these complexes, including cytotoxicity and subcellular localization, has been measured. Unlike earlier generations of metalloinsertors, even the most lipophilic complexes in this family do not exhibit excessive off-target mitochondrial localization, allowing them to maintain high selective cytotoxicity towards MMR deficient cells and reduced off-target cytotoxicity in MMR proficient cells. Overall, the biol. activity of metalloinsertors contg. this Rh-O ligand coordination appears to be highly robust regardless of substitution of the ancillary ligands. This ligand framework could serve as an excellent scaffold for future conjugation to cytotoxic or fluorescent payloads for therapeutic or diagnostic use