Natural Enantiomer Research Articles

An Internally Attached Aptameric Graphene Nanosensor for Sensitive Vasopressin Measurement in Critical Patient Monitoring.

This paper presents an aptameric graphene nanosensor for rapid and sensitive measurement of arginine vasopressin (AVP) toward continuous monitoring of critical care patients. The nanosensor is a field-effect transistor (FET) with monolayer graphene as the conducting channel and is functionalized with a new custom-designed aptamer for specific AVP recognition. Binding between the aptamer and AVP induces a change in the carrier density in the graphene and resulting in measurable changes in FET characteristics for determination of the AVP concentration. The aptamer, based on the natural enantiomer D-deoxyribose, possess optimized kinetic binding properties and is attached at an internal position to the graphene for enhanced sensitivity to low concentrations of AVP. Experimental results show that this aptameric graphene nanosensor is highly sensitive (with a limit of detection of 0.3 pM and a resolution of 0.1 pM) to AVP, and rapidly responsive (within 90 s) to both increasing and decreasing AVP concentration changes. The device is also reversable (within 4%), repeatable (within 4%) and reproducible (within 5%) in AVP measurements.

The Vitamin C Enantiomers Possess a Comparable Potency in the Induction of Oxidative Stress in Cancer Cells but Differ in Their Toxicity.

The use of vitamin C (VC) in high doses demonstrates a potent tumor suppressive effect by mediating a glucose-dependent oxidative stress in Kirsten rat sarcoma (KRAS) mutant cancer cells. VC with arsenic trioxide (ATO) is a promising drug combination that might lead to the development of effective cancer therapeutics. Considering that a tumor suppressive effect of VC requires its high-dose administration, it is of interest to examine the toxicity of two enantiomers of VC (enantiomer d-optical isomer D-VC and natural l-optical isomer L-VC) in vitro and in vivo. We show that the combinations of L-VC with ATO and D-VC with ATO induced a similar cytotoxic oxidative stress in KrasG12D-expressing mutant cancer cells as indicated by a substantial increase in reactive oxidative species (ROS) production and depolarization of mitochondria. To examine the L-VC and D-VC toxicity effects, we administered high doses of D-VC and L-VC to CD1 mice and carried out an evaluation of their toxic effects. The daily injections of L-VC at a dose of 9.2 g/kg for 18 days were lethal to mice, while 80% of mice remained alive following the similar high-dose administration of D-VC. Following the drug injection courses and histopathological studies, we determined that a natural form of VC (L-VC) is more harmful and toxic to mice when compared to the effects caused by the similar doses of D-VC. Thus, our study indicates that the two enantiomers of VC have a similar potency in the induction of oxidative stress in cancer cells, but D-VC has a distinctive lower toxicity in mice compared to L-VC. While the mechanism of a distinctive toxicity between D-VC and L-VC is yet to be defined, our finding marks D-VC as a more preferable option compared to its natural enantiomer L-VC in clinical settings.

Synthesis and Evaluation of Natural and Unnatural Tetrahydrocannabiorcol for Its Potential Use in Neuropathologies.

(-)-trans-Δ9-Tetrahydrocannabinol (trans-(-)-Δ9-THC) has shown neuroprotective potential, but its medicinal benefits are not fully exploited due to the limitations of psychoactive properties. The lower homologues are non-psychoactive in nature but lack comprehensive scientific validation regarding neuroprotective potential. The present study describes the synthesis of non-psychoactive lower homologues of THC-type compounds and their neuroprotective potential. Both natural tetrahydro-cannabiorcol (trans-(-)-Δ9-THCO) and unnatural Δ9-tetrahydrocannabiorcol (trans-(+)-Δ9-THCO) were successfully synthesized starting from R-limonene and S-limonene, respectively, and investigated for neuroprotective potential in cellular models. The structures of both enantiomers were confirmed by NMR, HMBC, HQSC, NOESY, and COSY experiments. Results indicated that both enantiomers were nontoxic to the cells treated up to 50 μM. Neuroprotective properties of the enantiomers showed that treatments could significantly reverse the corticosterone-induced toxicity in SH-SY5Y cells and simultaneously cause elevated expression of brain-derived neurotrophic factor (BDNF). It was also observed that unnatural trans-(+)-Δ9-THCO displayed better activity than the natural enantiomer and can be further explored for its potential use in neuropathological ailments.

Bioactive monoterpenoids and acetophenones from the aerial parts of Eupatorium fortunei

Thirty-nine thymol and acetophenone derivatives, including eight pairs of enantiomers, were isolated from the aerial parts of Eupatorium fortunei. Their structures were assigned by detailed analyses of spectroscopic data and NMR calculations based on density functional theory, with 18 ones (1a/1b−14) being previously undescribed compounds. While the absolute configurations of 1a/1b, 2a/2b, 4, 6a/6b, 7, 11a/11b and 15a/15b−18a/18b were established by calculations of electronic circular dichroism data, that of 14 was determined by modified Mosher's method. Compounds 1a/1b and 2a/2b represent a previously unreported type of monoterpenoid dimers via an amide linkage, and compound 3 is a monoterpene-phenylpropanoid hybrid connected through an ester bond. Among the known molecules, the formerly mis-assigned structures of 15a/15b and 22 were revised, and pure natural enantiomers of 16a/16b−18a/18b were reported for the first time. Selective compounds showed antiradical and NO production inhibitory activities in the preliminary biological screening. Compound 31 was further demonstrated to alleviate oxidative stress by activating Nrf2 signaling pathway.

Investigation of a novel approach to the core of stemofoline: enantioselective construction of a bicyclic intermediate with three contiguous chiral centers

<p indent="0mm">The enantioselective synthesis of a bicyclic intermediate containing three contiguous chiral centers for a novel approach to the core of stemofoline is described. A (<italic>S</italic>)-malimide derivative developed in this laboratory was used as the chiral building block. The latter was converted in three steps (<italic>N</italic>-deprotection, a Mitsunobu reaction, and a cross-olefin metathesis) into another malimide with the <italic>N</italic>-substituent bearing a nucleophilic allylic silane moiety. The Grignard reagent addition took place regioselectively at the C-2 carbonyl to yield a hemiaminal. The key intramolecular aza-Sakurai reaction was promoted by trifluoroboron etherate, which led to the desired cyclization in good to excellent combined yields. Four diastereomers were formed from this reaction, whose stereochemistries were determined by NOESY technique. The latter revealed that the major diastereomer (obtained in 35% yield) possessed the correct stereochemistries required for the total synthesis of natural enantiomer of stemofoline. A regioselective Wacker oxidation resulted in the formation of the title compound along with a minor regioisomer (an aldehyde) in a ratio of 18: 1 (combined yield: 50%).

Immunomodulatory Effects of (R)-Sulforaphane on LPS-Activated Murine Immune Cells: Molecular Signaling Pathways and Epigenetic Changes in Histone Markers.

The aim of this study was to explore the immunomodulatory effects of the natural enantiomer (R)-Sulforaphane (SFN) and the possible signaling pathways involved in an ex vivo model of LPS-stimulated murine peritoneal macrophages. Furthermore, we studied the epigenetic changes induced by (R)-SFN as well as the post-translational modifications of histone H3 (H3K9me3 and H3K18ac) in relation to the production of cytokines in murine splenocytes after LPS stimulation. (R)-SFN was able to modulate the inflammatory response and oxidative stress induced by LPS stimulation in murine peritoneal macrophages through the inhibition of reactive oxygen species (ROS), nitric oxide (NO) and cytokine (IL-1β, IL-6, IL-17, IL-18 and TNF-α) production by down-regulating the expression of pro-inflammatory enzymes (iNOS, COX-2 and mPGES-1). We also found that activation of the Nrf-2/HO-1 axis and inhibition of the JAK2/STAT-3, MAPK, canonical and non-canonical inflammasome signaling pathways could have been responsible for the immunomodulatory effects of (R)-SFN. Furthermore, (R)-SFN modulated epigenetic modifications through histone methylation (H3K9me3) and deacetylation (H3K18ac) in LPS-activated spleen cells. Collectively, our results suggest that (R)-SFN could be a promising epinutraceutical compound for the management of immunoinflammatory diseases.

Can Weak Chirality Induce Strong Coupling between Resonant States?

Strong coupling between resonant states is usually achieved by modulating intrinsic parameters of optical systems, e.g., the refractive index of constituent materials or structural geometries. Externally introduced chiral enantiomers may couple resonances, but the extremely weak chirality of natural enantiomers largely prevents the system from reaching strong coupling regimes. Whether weak chirality could induce strong coupling between resonant states remains an open question. Here, we realize strong coupling between quasibound states in the continuum of a high-Q metasurface, assisted with externally introduced enantiomers of weak chirality. We establish a chirality-involved Hamiltonian to quantitatively describe the correlation between the coupling strength and the chirality of such systems, which provides an insightful recipe for enhancing the coupling of resonant states further in the presence of quite weak chirality. Consequently, high-sensitivity chiral sensing is demonstrated, in which the circular dichroism signal is enhanced 3 orders higher than the case without strong coupling. Our findings present a distinct strategy for manipulating optical coupling between resonances, revealing opportunities in chiral sensing, topological photonics, and quantum optics.

In vivo Structure-Activity Relationship of Dihydromethysticin in Reducing Nicotine-Derived Nitrosamine Ketone (NNK)-Induced Lung DNA Damage against Lung Carcinogenesis in A/J Mice.

Lung cancer is the leading cause of cancer-related deaths and chemoprevention should be developed. We recently identified dihydromethysticin (DHM) as a promising candidate to prevent NNK-induced lung tumorigenesis. To probe its mechanisms and facilitate its future translation, we investigated the structure-activity relationship of DHM on NNK-induced DNA damage in A/J mice. Twenty DHM analogs were designed and synthesized. Their activity in reducing NNK-induced DNA damage in the target lung tissues was evaluated. The unnatural enantiomer of DHM was identified to be more potent than the natural enantiomer. The methylenedioxy functional moiety did not tolerate modifications while the other functional groups (the lactone ring and the ethyl linker) accommodated various modifications. Importantly, analogs of high structural similarity to DHM with distinct efficacy in reducing NNK-induced DNA damage have been identified. They will serve as chemical probes to elucidate the mechanisms of DHM in blocking NNK-induced lung carcinogenesis.

Total Asymmetric Synthesis and Stereochemical Confirmation of (+)- and (-)-Lyoniresinol and Its Deuterated Analogues.

Lyoniresinol and its derivatives are lignans which have been isolated from a plethora of plant species. In addition to exhibiting a range of interesting biological activities including anticancer, anti-inflammatory, antimicrobial, and others, these compounds have also been discovered in wines and spirits and shown to have gustatory effects in these alcoholic matrices. (+)-Lyoniresinol 1 is reported to impart a strong bitter taste while its enantiomer (-)-lyoniresnol 2 is tasteless. The first total asymmetric synthesis of both natural enantiomers (+)-1 and (-)-2 and their deuterated analogues (D4)-(+)-3 and (D4)-(-)-4 has been achieved, confirming the structure and stereochemistry of the natural products. The synthesized compounds can be utilized as internal standards in stable isotope dilution analysis for improving and optimizing the existing lyoniresinol quantitation methods in the future.

Natural Enantiomers: Occurrence, Biogenesis and Biological Properties.

The knowledge that natural products (NPs) are potent and selective modulators of important biomacromolecules (e.g., DNA and proteins) has inspired some of the world’s most successful pharmaceuticals and agrochemicals. Notwithstanding these successes and despite a growing number of reports on naturally occurring pairs of enantiomers, this area of NP science still remains largely unexplored, consistent with the adage “If you don’t seek, you don’t find”. Statistically, a rapidly growing number of enantiomeric NPs have been reported in the last several years. The current review provides a comprehensive overview of recent records on natural enantiomers, with the aim of advancing awareness and providing a better understanding of the chemical diversity and biogenetic context, as well as the biological properties and therapeutic (drug discovery) potential, of enantiomeric NPs.

Identification of Cuticular and Web Lipids of the Spider Argiope bruennichi

Emerging evidence shows that the cuticular and silk lipids of spiders are structurally more diverse than those of insects, although only a relatively low number of species have been investigated so far. As in insects, such lipids might play a role as signals in various contexts. The wasp spider Argiope bruennichi has probably the best investigated chemical communication system within spiders, including the known structure of the female sex pheromone. Recently we showed that kin-recognition in A. bruennichi could be mediated through the cuticular compounds consisting of hydrocarbons and, to a much larger proportion, of wax esters. By use of mass spectrometry and various derivatization methods, these were identified as esters of 2,4-dimethylalkanoic acids and 1-alkanols of varying chain lengths, such as tetradecyl 2,4-dimethylheptadecanoate. A representative enantioselective synthesis of this compound was performed which proved the identifications and allowed us to postulate that the natural enantiomer likely has the (2R,4R)-configuration. Chemical profiles of the silk and cuticular lipids of females were similar, while male cuticular profiles differed from those of females. Major components of the male cuticular lipids were tridecyl 2,4-dimethyl-C17-19 alkanoates, whereas those of females were slightly longer, comprising tridecyl 2,4-dimethyl-C19-21 alkanoates. In addition, minor female-specific 4-methylalkyl esters were detected.

Pheromone Chemistry of the Citrus Borer, Diploschema rotundicolle (Coleoptera: Cerambycidae).

The citrus borer, Diploschema rotundicolle, is a Neotropical longhorn beetle that has become a serious citrus pest in southern South America. Management strategies for this insect rely on trimming off damaged shoots, which is expensive and inefficient. We studied the chemical communication system in D. rotundicolle in search of attractants for monitoring or control. GC-MS and enantioselective GC analyses of volatile extracts from field-collected adults showed that males produce (R)-3-hydroxy-2-hexanone, irregularly accompanied by minor amounts of 2,3-hexanediol (all four stereoisomers) and 2,3-hexanedione. Males emit the compounds only at night, when the adults are active. GC-EAD analyses of natural and synthetic compounds showed that both male and female antennae respond to the natural enantiomer (R)-3-hydroxy-2-hexanone, suggesting that it may function as an aggregation-sex pheromone as seen in many cerambycines. The non-natural (S) enantiomer as well as the minor component 2,3-hexanediol did not trigger antennal responses. Field tests with the racemic 3-hydroxy-2-hexanone, enantiomerically pure (R)-3-hydroxy-2-hexanone, as well as a mixture of racemic 3-hydroxy-2-hexanone and 2,3-hexanediol, showed in all cases low capture levels of D. rotundicolle. However, increasing the elevation of the trap and the emission rate of dispensers enhanced field captures in traps baited with racemic hydroxyketone. Incidental catches of another native cerambycine, Retrachydes thoracicus, in traps baited with 3-hydroxy-2-hexanone are also reported. This is the first report of pheromone chemistry in the genus Diploschema and in the tribe Torneutini, reaffirming the pheromone parsimony well established for the Cerambycinae. Potential factors explaining the weak attraction of D. rotundicolle in the field are discussed.

Enantioselective synthesis and determination of the absolute configuration of the male sex pheromone of the parasitoid wasp Urolepis rufipes.

Males of the parasitoid wasp Urolepis rufipes use 2,6-dimethyl-7-octene-1,6-diol as a sex pheromone to attract virgin females. Herein, we determine the absolute configuration of the pheromone to be (2S,6S)-2,6-dimethyl-7-octene-1,6-diol (2S,6S-6) and present a stereoselective synthesis of the natural enantiomer of this new linalool derivative. In addition, we show that female wasps respond to the natural 2S,6S-6 stereoisomer while 2R,6S-6 is behaviorally inactive.

Optimizing pheromone-based lures for the invasive red-necked longhorn beetle, Aromia bungii

Aromia bungii is a serious pest of stone fruit trees including cherries, plums, peaches and apricots. It is native to eastern Asia but has recently been introduced into and has established in Japan, Germany and Italy and has been intercepted in cargo entering the USA and Great Britain. We synthesized the naturally produced enantiomer of the major pheromone component, (E)-2-cis-6,7-epoxynonenal, and in field tests, comparing its attractiveness to that of the racemate. We also tested different ratios of a minor pheromone component, (2E,6Z)-nona-2,6-dienal, on attraction to the major component. Lastly, we conducted a dose–response assay to determine the optimal loading rates. Addition of the minor component at a ratio of 0.31 mg minor to 25 mg major component is more than double the trap captures of males but not females. Using this ratio, we found no difference in trap captures with 10 mg, 32 mg or 100 mg of the major component, but the 10 mg load attracted significantly more females than the 3.2 mg load, and only the 32 mg load attracted significantly more males than the 3.2 mg load. The natural enantiomer was significantly more attractive to females than the racemate. However, the multi-step, low-yielding synthesis likely will prohibit the insect-produced enantiomer from being used for operational trapping. The addition of the minor component to the racemate significantly increased trap catches, and the dose–response assay did not indicate significant differences in loads above 10 mg of the racemic major component when formulated with ~ 1.2% of the minor component.

The Ambidextrous Pictet–Spengler Reaction: Access to the (+)- or (–)-Enantiomers of the Bioactive C-19 Methyl-Substituted Sarpagine/Macroline/Ajmaline Alkaloids from Either d- or l-Tryptophan

Depicted in the following is the proof of concept, which is important to illustrate the full potential of the ambidextrous Pictet–Spengler (P-S) reaction. Previously, both d-tryptophan and l-tryptophan were employed to synthesize the key intermediates toward the natural enantiomers of C-19 methyl-substituted alkaloids. Now the enantiomeric series of the same key intermediates could also be synthesized from both d- or l-tryptophan in high yield and optical purity via this P-S/Dieckmann protocol. One can make either the natural or the unnatural alkaloids from either of the chiral starting amino acid esters, stereo- and enantiospecifically for biological screening.

Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine.

Phantasmidine, a rigid congener of the well-known nicotinic acetylcholine receptor agonist epibatidine, is found in the same species of poison frog ( Epipedobates anthonyi). Natural phantasmidine was found to be a 4:1 scalemic mixture, enriched in the (2a R,4a S,9a S) enantiomer by chiral-phase LC-MS comparison to the synthetic enantiomers whose absolute configurations were previously established by Mosher's amide analysis. The major enantiomer has the opposite S configuration at the benzylic carbon to natural epibatidine, whose benzylic carbon is R. Pharmacological characterization of the synthetic racemate and separated enantiomers established that phantasmidine is ∼10-fold less potent than epibatidine, but ∼100-fold more potent than nicotine in most receptors tested. Unlike epibatidine, phantasmidine is sharply enantioselective in its activity and the major natural enantiomer whose benzylic carbon has the 4a S configuration is more active. The stereoselective pharmacology of phantasmidine is ascribed to its rigid and asymmetric shape as compared to the nearly symmetric conformations previously suggested for epibatidine enantiomers. While phantasmidine itself is too toxic for direct therapeutic use, we believe it is a useful platform for the development of potent and selective nicotinic agonists, which may have value as pharmacological tools.

Total Synthesis of Clavilactones.

Clavilactones A, B, and D are epidermal growth factor receptor tyrosine kinase inhibitors that were isolated from cultures of the fungus Clitocybe clavipes. Here, we report full details of the total synthesis of these clavilactones. A key feature of our synthetic approach is a ring-opening/ring-closing metathesis strategy that allows the concise transformation of a cyclobutenecarboxylate into a γ-butenolide. Coupled with enantioselective Ti/BINOL-catalyzed alkynylation of a multisubstituted benzaldehyde and ring-closing metathesis of a diene-bearing silylene acetal to construct the 10-membered carbocycle, this strategy enabled the total synthesis of the natural enantiomers (+)-clavilactone A and (-)-clavilactone B. In addition, the correct structure of clavilactone D was determined by the synthesis of two newly proposed structures. This research resulted in the asymmetric synthesis of the revised (+)-clavilactone D.

Abstract 2622: Two new TLR9 agonists for cancer immunotherapy: Combination with checkpoint inhibitors

Abstract Introduction TLR9 agonists are developed as anti-cancer therapies based on their broad activation of the innate and adaptive immune system. Single-stranded oligodeoxynucleotides (ODN) containing non-methylated CG-motifs activate TLR9. Previously, chemical modification was used to prevent their degradation by exonucleases. To avoid the off-target effects observed with chemical modifications, new TLR9 agonists containing only natural DNA were stabilized by structural components. The dSLIM® family of TLR9 agonists is protected from exonucleolytic degradation by its covalently-closed dumbbell-shaped structure. It contains an immunomodulatory sequence with CG-motifs in its loops. The linear single-stranded EnanDIM® family of TLR9 agonists utilizes L-deoxyribonucleotides (natural enantiomers of D-deoxyribonucleotides) at their 3’-ends to prevent degradation. Since the mode-of-action of TLR9 agonists starts upstream of the targets of checkpoint inhibitors anti-PD-1/anti-PD-L1 a combinatory approach may support synergistic immune activation and thus enhanced anti-tumor effects. Methods The impact of dSLIM2006 and EnanDIM-1 on T cell responses was analyzed employing an in vitro assay using human peripheral blood mononuclear cells (PBMC). PBMC were treated with peptides selected from HLA class I-restricted T-cell epitopes of recall-antigens (CMV, EBV, Flu = CEF), TLR9 agonists and anti-PD-1 as checkpoint inhibitor. In addition, in vivo studies were used to investigate the anti-tumor effect of dSLIM2006 and EnanDIM-1 in combination with anti-PD-1 in a syngeneic murine CT26 tumor model. Results The IFN-gamma secretion of human PBMC after stimulation of CEF peptides was roughly 5-fold increased by EnanDIM-1 and dSLIM2006, whereas treatment with anti-PD-1 resulted barely in a two-fold increase. The combination of the TLR9 agonists and anti-PD-1 further enforced IFN-gamma secretion by about 7-fold. In the murine colon cancer model CT26 the subcutaneous injection of EnanDIM-1 or intraperitoneal injection of anti-PD-1 had a moderate effect on the tumor growth when used in monotherapy (28.3% or 57.0% tumor growth inhibition, TGI). Notably, a combination of EnanDIM-1 and anti-PD-1 further reduced tumor growth (74.7% TGI). Intratumoral injection of dSLIM2006 in combination with intraperitoneal injection of anti-PD-1 reduced tumor growth (54.2% TGI) whereas the single components had more limited effects (dSLIM2006: 18.7%, anti-PD-1: no inhibition). Combined treatment with TLR9 agonists and anti-PD-1 prolonged survival of the mice in comparison to single treatments. Conclusions The TLR9 agonists and immune surveillance reactivators (ISR) EnanDIM-1 and dSLIM2006 enhance T cell responses and anti-tumor effects of the anti-PD-1 checkpoint inhibitor. These data show their promising potential not only for monotherapeutic but also combinatory approaches. Citation Format: Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt. Two new TLR9 agonists for cancer immunotherapy: Combination with checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2622. doi:10.1158/1538-7445.AM2017-2622

Combination of TLR9 agonists EnanDIM with checkpoint inhibitors for cancer immunotherapy.

134 Background: TLR9 agonists have shown anti-tumor effects by modulating the innate and adaptive immune system. Ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. The new family of TLR9 agonists, EnanDIM, consists of linear single-stranded ODN synthesized using L-deoxyribonucleotides (natural enantiomers of D-deoxyribonucleotides) at their 3’-ends to prevent degradation. Therefore, EnanDIM does not own the off-target effects of PTO-modified CpG-ODN. Methods: EnanDIM with varying nucleotid sequences were compared for IFN-alpha response from human peripheral blood mononuclear cells and those molecules inducing the stronges response were selected. A maximum feasible dose (MFD) approach was employed to evaluate their acute toxicity and immunomodulatory properties. In addition, a combinatory approach with aPD-1 was evaluated in an syngeneic colon carcinoma CT26 mouse tumor model. Results: EnanDIM581 and EnanDIM532 were selected due to their pronounced activation of the IFN-alpha pathway in vitro. Safety assessments throughout and a gross necropsy at the end of the study revealed no signs of toxicity despite extremely high doses (300 - 1700 mg/kg). Dose-dependent increase of IP-10 levels in serum was observed between 6 and 24 hours after injection. In the colon carcinoma CT26 model subcutaneous injection of EnanDIM532 and intraperitoneal injection of aPD-1 had a moderate effect on the tumor growth when used in monotherapy (28.3% and 57.0% tumor growth inhibition, TGI). Notably, a combination of EnanDIM532 and aPD-1 further reduced tumor growth (74.7% TGI) and thus prolonged survival of the mice. Conclusions: In conclusion, EnanDIM, a new family of TLR9 agonists and immune surveillance reactivators (ISR), broadly activates the immune system, shows no toxicity in an MFD study and enhances the anti-tumor effects of the aPD-1 checkpoint inhibitor in a pilot study of a murine colon carcinoma tumor model. These data show the promising potential of EnanDIM not only for monotherapeutic but also combinatory approaches.

Enantioselective Conversion of Achiral Cyclohexadienones to Chiral Cyclohexenones by Desymmetrization.

The enantioselective reduction of prochiral 4,4-disubstituted 2,5-cyclohexadienones to chiral 2-cyclohexenones has been accomplished by the use of a carefully selected chiral bisphosphine-CuI complex and diisobutylaluminum hydride-hexamethylphosphoric triamide complex. This reagent has provided access to a key bicyclic intermediate for the total synthesis of the natural enantiomer of the pentacyclic sesterterpene retigeranic acid that involves spatial discrimination between CH3 and CH2CH2R substituents, an operation that has been elusive previously. In addition, a second method for desymmetrization is described using catalytic enantioselective [4 + 2]-cycloaddition of cyclopentadiene to prochiral 4,4-disubstituted 2,5-cyclohexadienones.