Key Points • Nanatinostat plus valganciclovir is a novel oral regimen for relapsed/refractory EBV+ lymphoma that warrants further investigation.• Encouraging efficacy and safety were observed across a variety of EBV+ lymphoma subtypes.

Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706).

In the presence of pyridine, at -5 degrees C, lipase TL (R)-mediated kinetic resolution of (+/-)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)-propan-2-ol was found to proceed efficiently to give the corresponding (S)-alcohol and (R)-acetate, each with high enantiomeric excess and in quantitative yield. The alcohol (S)-1 and the acetate (R)-2-derived alcohol, (R)-1, could be converted to the 1-protected glycerols with either of the stereochemistry by the choice of the deprotection of the protective groups. (C) 2021 Elsevier Ltd. All rights reserved.

Fifteen new isopimarane-type diterpenes, taichunins E-S (1-15), and a new 20-nor-isopimarane, taichunin T (16), together with four known compounds were isolated from Aspergillus taichungensis (IBT 19404). The structures of these new compounds were determined by NMR and mass spectroscopy, and their absolute configurations were analyzed by NOESY and TDDFT calculations of ECD spectra. Taichunins G, K, and N (3, 7, and 10) completely inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts in RAW264 cells at 5 μM, with 3 showing 92% inhibition at a concentration of 0.2 μM.

This chapter examines the emergence of craft beer as a noteworthy component of gastro-tourism. A grounded theory approach over a 2-year period (2017–2019) established the research and analysis framework, and provided the findings reported in this chapter. Our research has confirmed that: (1) large, global conglomerates; (2) national craft beer brands with bicoastal or multilocations; and (3) local boutique craft beer establishments are appealing to sought-after tourist attractions within their geographic locales. This chapter identified six aspects that optimize craft brewery–tourism relationships and six brewery-specific hospitality features, regardless of brewery type. Ultimately, a brewery-driven gastro-tourism development (12-point) model was developed to illustrate how craft breweries of all sizes contribute to the overall gastronomic reputation and highlight how the open, friendly, inclusive, brewery ethos, or gastro-communitas can help to positively shape an area's overall unique local tourism culture—the area's unique story!

New structural classes of antibiotics are rare, structurally novel broad-spectrum antibiotics exceptionally so. The recently discovered baulamycins constitute a remarkable example of these highly prized compounds and, as such, have attracted considerable attention in the form of both synthetic efforts and biological studies. For the first time, we report a gram-scale preparation of the common carbon framework of the baulamycin family, as well as the total synthesis of its most potent member, baulamycin A. Our approach employs highly stereoselective, catalyst-controlled asymmetric conjugate additions to thioesters to set key stereocenters, as well as the first reported use of "dry ozonolysis" to reveal a masked carboxylic acid in the total synthesis of a natural product.

The fungal indole alkaloids are a unique class ofcomplex molecules that have a characteristic bicyclo[2.2.2]diazaoctane ring and frequently contain a spiro-oxindole moiety. While various strains produce these compounds,an intriguing case involves the formation of individual antipodes bytwo unique species of fungi in the generation of the potentanticancer agents (+)- and (-)-notoamide A. NotI and NotI′ havebeen characterized as flavin-dependent monooxygenases thatcatalyze epoxidation and semi-Pinacol rearrangement to form thespiro-oxindole center within these molecules. This work elucidatesa key step in the biosynthesis of the notoamides and provides anevolutionary hypothesis regarding a common ancestor forproduction of enantiopure notoamides.

The paraherquamides are potent anthelmintic natural products with complex heptacyclic scaffolds. One key feature of these molecules is the spiro-oxindole moiety that lends a strained three-dimensional architecture to these structures. The flavin monooxygenase PhqK was found to catalyze spirocycle formation through two parallel pathways in the biosynthesis of paraherquamides A and G. Two new paraherquamides (K and L) were isolated from a ΔphqK strain of Penicillium simplicissimum, and subsequent enzymatic reactions with these compounds generated two additional metabolites paraherquamides M and N. Crystal structures of PhqK in complex with various substrates provided a foundation for mechanistic analyses and computational studies. While it is evident that PhqK can react with various substrates, reaction kinetics and molecular dynamics simulations indicated that the dioxepin-containing paraherquamide L was the favored substrate. Through this effort, we have elucidated a key step in the biosynthesis of the paraherquamides, and provided a rationale for the selective spirocyclization of these powerful anthelmintic agents.

The notoamides are a fascinating class of anticancer natural products where two phylogenetically related fungal strains have evolved to generate enantiomeric (mirror image) terminal products. A study of the enzymes (NotI/NotI′) responsible for spirocycle formation revealed their differential flexibility in accepting the opposite substrate and catalyzing formation of the respective spiro-oxindole product. The preferential conversion of (−)-stephacidin A by both enzymes suggests an evolutionary divergence from a common ancestor that was selective for (+)-notoamide B/A production. More information can be found in the full paper by R. M. Williams, D. H. Sherman, et al.

Fungal bicyclo[2.2.2]diazaoctane indole alkaloids represent an important family of natural products with a wide spectrum of biological activities. Although biomimetic total syntheses of representative compounds have been reported, the details of their biogenesis, especially the mechanisms for the assembly of diastereomerically distinct and enantiomerically antipodal metabolites, have remained largely uncharacterized. Brevianamide A represents a basic form of the subfamily bearing a dioxopiperazine core and a rare 3-spiro-ψ-indoxyl skeleton. In this study, we have identified the brevianamide A biosynthetic gene cluster from Penicillium brevicompactum NRRL 864 and elucidated the metabolic pathway. BvnE was revealed to be an essential isomerase/semipinacolase that specifies the selective production of the natural product. Structural elucidation, molecular modelling and mutational analysis of BvnE as well as quantum chemical calculations have provided mechanistic insights into the diastereoselective formation of the 3-spiro-ψ-indoxyl moiety in brevianamide A. This occurs through a BvnE-controlled semipinacol rearrangement and a subsequent spontaneous intramolecular [4+2] hetero-Diels–Alder cycloaddition.

BACKGROUND: EBV-positive (EBV+) lymphomas including Hodgkin, B and T cell lymphomas, are generally associated with poor clinical outcomes, particularly for patients (pts) who have relapsed or are refractory (R/R) to standard therapies. There are currently no approved therapies for EBV+ lymphomas and with the exception of adoptive T-cell therapies, no EBV-targeted anti-lymphoma therapeutics are in development. EBV is detectable in cancer cells by in situ hybridization for EBV-encoded RNAs (EBER-ISH). Nstat (VRx-3996), a Class I-selective oral hydroxamate histone deacetylase (HDAC) inhibitor active against HDAC1-3, induces the expression of EBV protein kinases which activate the anti-viral nucleoside analogue VGCV via mono-phosphorylation. This leads to inhibition of both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells as well (bystander effect), causing apoptosis. This trial is the first to explore the safety and clinical activity of this targeted approach using oral Nstat in combination with oral VGCV in pts with R/R EBV+ lymphomas. Here we present an update of safety and efficacy for all enrolled patients, plus the preliminary safety of the recommended phase 2 doses (RP2D) of Nstat and VGCV (NCT03397706). METHODS: Pts with biopsy-proven EBV+ lymphomas (by EBER-ISH; any positive tumor cell) that had failed ≥1 prior systemic therapy and lacked treatment options by investigator's judgment were eligible for enrollment. Phase 1b used a 3x3 design to determine the RP2D of Nstat + VGCV. Phase 2 pts received the RP2D (Nstat 20 mg days (d) 1-4/7 + VGCV 900 mg orally daily in 28 d cycles) until PD or withdrawal. Primary endpoints were safety/RP2D selection (phase 1b) and ORR (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response (TTR), progression free survival (PFS) and overall survival (OS). Response assessments began after Cycle 2 using Lugano 2014 response criteria. RESULTS: As of 5 July 2020, 43 pts have enrolled (phase 1b: 25; phase 2: 18). Lymphoma subtypes were diffuse large B cell (DLBCL) (6), extranodal NK/T-cell (ENKTL) (6), peripheral T cell, NOS (PTCL-NOS) (3), angioimmunoblastic (AITL) (4), cutaneous T cell (CTCL) (1), Hodgkin (HL) (8), other B cell (2), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (13), including post-transplant lymphoproliferative disorder (PTLD) (4), HIV-associated (5), and other [4: systemic lupus erythematosus (SLE) (2), common variable immunodeficiency/primary immunodeficiency (2)]. Pts had a median of 2 prior therapies (range 1-11); 77% with ≥2 prior therapies, 86% were refractory to their most recent previous therapy and 77% had exhausted standard therapies in the judgment of the investigator. EBER positivity ranged from <1 to 80% in 18 pre-study tumor biopsies with central lab review. Most treatment-related AEs (TRAEs) were mild or moderate, most commonly thrombocytopenia (33%), nausea (29%), neutropenia (26%) and fatigue (24%). At the RP2D, 23 pts were evaluable for safety. The most frequent G3/4 TRAEs (in ≥5% of pts) were neutropenia (14%), anemia (9%), and nausea (9%). For all evaluable pts (n=34), the ORR was 44% (15/34), with 8 (24%) complete responses (CR). The median TTR was 53 d (range 44-161 d). Responses for the 10 evaluable T/NK-NHL pts (ORR/CR 80%/40%) are shown in Table 1 [ENKTL (n=5; 1 CR 3 PR); T cell (n=5; 3 CR 1 PR)]. Two pts (ENKTL and PTCL-NOS) in PR/CR respectively were withdrawn for autologous stem cell transplantation (ASCT). For DLBCL (n=6), ORR/CR was 66%/33% (both CRs were in pts refractory to first-line R-CHOP). For IA-LPD (predominantly B-cell), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). The median DoR for all responders is 10.6 months, with a median follow-up from response of 5.0 m (range 0.4-22.9 m). CONCLUSIONS: Co-administration of oral Nstat with VGCV has a favorable safety profile, may be suitable for combination with additional agents, and shows promising efficacy in pts with a variety of R/R, heavily pre-treated EBV+ lymphomas, the majority of whom were lacking therapeutic options. Preliminary data suggests that this regimen is highly active in EBV+ T/NK-NHL pts who are refractory to standard therapies, including ASCT (Table 1), and promising in EBV+ DLBCL. Thus far, no apparent correlation was noted between degree of EBER positivity in pre-study tumor biopsies and ORR. Disclosures Porcu: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy; Miragen: Research Funding; Kura Oncology: Research Funding; Kiowa Kirin: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Daiichi: Consultancy, Honoraria; Cell Medica: Research Funding; Celgene: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Alpdogan:Seattle Genetics: Consultancy; Kiowa Kirin: Consultancy. Baiocchi:viracta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Consultancy, Research Funding. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Feldman:AstraZeneca: Consultancy; Janssen: Speakers Bureau; Portola: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Brem:KITE: Consultancy; TG Therapeutics: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Pharmacyclics: Speakers Bureau. Scheinberg:Novartis Brasil S.A.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katkov:Viracta Therapeutics, Inc.: Current Employment. McRae:Viracta Therapeutics, Inc.: Current Employment. Rojkjaer:Viracta Therapeutics, Inc.: Current Employment. Royston:Viracta Therapeutics, Inc.: Current Employment. OffLabel Disclosure: Nanatinostat(VRx-3996) is a Class I-selective oral HDAC inhibitor active against HDAC1-3 that induces the expression of EBV protein kinases which activate the anti-viral nucleoside analogue VGCV via mono-phosphorylation. This leads to inhibition of both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells as well (bystander effect), causing apoptosis.

The stereospecific polycyclic core formation of hapalindoles and fischerindoles is controlled by the Stig cyclases through a three-step cascade involving Cope rearrangement, 6- exo -trig cyclization and a final electrophilic aromatic substitution. Here we report a comprehensive study of all currently annotated Stig cyclases, and reveal that these proteins can assemble into heteromeric complexes induced by Ca 2+ to cooperatively control the stereochemistry of hapalindole natural products.

A new isoindolinone alkaloid, irpexine (1), was isolated as a racemate, along with a known green pigment, hypoxyxylerone (2), from the coculture of two endophytic fungi, Irpex lacteus and Phaeosphaeria oryzae. Compound 1 was found to be a newly produced metabolite of I. lacteus in the coculture with P. oryzae. Although 2 was produced in a monoculture of I. lacteus, its production was markedly enhanced by the coculture.

Fungal bicyclo[2.2.2]diazaoctane indole alkaloids demonstrate intriguing structures and a wide spectrum of biological activities. Although biomimetic total syntheses have been completed for representative compounds of this structural family, the details of their biogenesis have remained largely uncharacterized. Among them, Brevianamide A represents the most basic form within this class bearing a dioxopiperazine core structure and a rare 3-spiro-psi-indoxyl skeleton. Here, we identified the Brevianamide A biosynthetic gene cluster from Penicillium brevicompacticum NRRL 864 and fully elucidated the metabolic pathway by targeted gene disruption, heterologous expression, precursor incorporation studies, and in vitro biochemical analysis. In particular, we determined that BvnE is a cofactor-independent isomerase that is essential for selective production of Brevianamide A. Based on a high resolution crystal structure of BvnE, molecular modeling, mutational analysis, and computational studies provided new mechanistic insights into the diastereoselective formation of the 3-spiro-psi-indoxyl moiety in Brevianamide A. This occurs through a biocatalyst controlled semi-Pinacol rearrangement and a subsequent spontaneous intramolecular [4+2] hetero-Diels-Alder cycloaddition.

Background: EBV-positive (EBV+) cells are detectable in a variable but significant fraction of lymphomas of all lineages and histologic type by in situ hybridization for EBV-encoded RNA (EBER-ISH). EBV positivity generally confers a worse prognosis in lymphoma but, with the exception of adoptive T-cell therapies, no EBV-targeting mechanism-based anti-lymphoma therapeutics are in development. EBV's DNA genome encodes a viral thymidine kinase (vTK, BXLF1) and a serine/threonine protein kinase (PK, BGLF4), which are expressed only during lytic cycle, and can activate anti-viral nucleoside analogues via mono-phosphorylation, leading to inhibition of EBV DNA synthesis. Nstat is able to induce the expression of PK/BGLF4 and vTK/BXLF1. This effect supports the mechanism-based strategy of leveraging EBV's presence in lymphoma by combining Nstat with VGCV, the oral prodrug for ganciclovir (GCV). EBV's PK phosphorylates GCV, which inhibits both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells (bystander effect). Based on this targeted approach, a phase 1b/2a trial was launched to determine the safety and activity of this combination in R/R EBV+ lymphomas of various lineages and histology. Here we report the phase 1b results. Methods: Eligible patients had biopsy-proven R/R EBV+ lymphoma by EBER-ISH (any positive cell) and had failed ≥1 prior systemic therapy. Phase 1b followed a 3+3 design over 5 dose ranging cohorts. The phase 1b primary objectives were safety/tolerability of Nstat/VGCV and recommended phase 2 dose (RP2D). In cohorts 1-4, variable doses of Nstat and VGCV were administered orally continuously on 28-day cycles. In cohort 5 Nstat was administered for the first 4 days of each week with daily VGCV. Toxicity was assessed by CTCAE 5.0. Efficacy was assessed by local and central radiology every 2 cycles by PET/CT (Lugano 2014 Classification). Correlative studies for phase 1b include PK/PD and other exploratory biomarkers. Results: Phase 1b enrolled 25 patients. The median age was 58 (19-84) with 72% males. Thirteen patients had either EBV+ T/NK-cell lymphoma (N=8; 5 TCL, 3 NKL), or Hodgkin lymphoma (HL) (N=5). Twelve patients had EBV+ B-cell lymphoma (BCL) (Table 1), of which 4 were HIV+ and 3 had a history of PTLD. Median number of prior therapies was 2 (1-9). Two patients with TCL had failed prior HDACi therapy. In cohorts 1-4, the most frequent treatment related hematologic grade 3-4 (G3-4) adverse events (AE) were thrombocytopenia (35%), neutropenia (25%), and lymphopenia (15%), none of which occurred at G3-4 in cohort 5. No non-hematologic G3-G4 AE were observed in >10% of patients in any cohort and no patient discontinued therapy due to AE. The RP2D was declared to be Nstat 20 mg days 1-4 each week and VGCV 900 mg daily on a 28-day cycle. At the RP2D there have been no G3-4AE. Seventeen patients are evaluable for response (8 BCL 5 T/NK, 4 HL). ORR was 53% (9/17), with 29% CRR (5/17). The Clinical Benefit Rate (CBR; CR/PR/Stable Disease) was 76% (13/17). Responses were seen across histologic subtypes and in heavily pre-treated patients. Durable responses were observed (one >12 months and one >10 months). For the 14 evaluable HIV-negative patients (5 BCL, 5 T/NK, 4 HL) ORR, CRR, and CBR were 64%, 36%, and 93%, respectively, with CRs and PRs in all histologic subtypes. The ORR was 3/5 for BCL (2 CR, 1 PR); 5/5 for T/NK (2 CR, 3 PR); and 1/4 in HL (1 CR). One BCL patient with combined variable immunodeficiency (CVID) achieved a CR. Only 1 of 3 BCL patients with a history of PTLD was evaluable and achieved a CR. All three evaluable HIV+ BCL patients progressed. Of 8 patients with detectable baseline plasma EBV DNA, 7 demonstrated a reduction (-17% to -83%). Other biomarker studies are in progress. Conclusion: In this phase 1b study, the combination of oral Nstat and VGCV was well tolerated in patients with EBV+ lymphomas, with no unexpected G3-G4 AE, and showed a very encouraging signal of efficacy, especially in HIV-negative patients, with CRs in BCL, TCL, and HL. The combination of Nstat and VGCV is a compelling targeted oral therapy for R/R EBV+ lymphomas of different lineage and histologic type and should be explored in other EBV+ malignancies. The phase 2a portion of this study is actively recruiting (NCT03397706). Disclosures Porcu: Viracta: Honoraria, Other: Scientific Board, Research Funding; Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Feldman:Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brem:Celgene: Honoraria, Speakers Bureau; BMS/Pfizer: Honoraria; Janssen: Honoraria, Speakers Bureau; Bayer: Honoraria; Genetech: Honoraria; Pharmacyclics: Honoraria, Speakers Bureau. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Barta:Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Trauger:Viracta: Employment. Gutheil:Viracta Therapeutics: Consultancy. Katkov:Viracta: Employment. McRae:Viracta: Employment. Royston:Viracta: Employment.

Prenylated indole alkaloids isolated from various fungi possess great structural diversity and pharmaceutical utility. Among them are the calmodulin inhibitory malbrancheamides and paraherquamides, used as anthelmintics in animal health. Herein, we report complete elucidation of the malbrancheamide biosynthetic pathway accomplished through complementary approaches. These include a biomimetic total synthesis to access the natural alkaloid and biosynthetic intermediates in racemic form, and in vitro enzymatic reconstitution that provides access to the natural antipode (+)-malbrancheamide. Reductive cleavage of a L-Pro-L-Trp dipeptide from the MalG nonribosomal peptide synthetase (NRPS) followed by reverse prenylation and a cascade of post-NRPS reactions culminates in an intramolecular [4+2] hetero-Diels-Alder (IMDA) cyclization to furnish the bicyclo[2.2.2]diazaoctane scaffold. Enzymatic assembly of optically pure (+)-premalbrancheamide involves an unexpected zwitterionic intermediate where MalC catalyzes enantioselective cycloaddition as a bifunctional NADPH-dependent reductase/Diels-Alderase. Crystal structures of substrate and product complexes together with site-directed mutagenesis and molecular dynamics simulations demonstrated how MalC and PhqE, its homolog from the paraherquamide pathway, catalyze diastereo- and enantioselective cyclization in the construction of this important class of secondary metabolites.

7551 Background: Nanatinostat (N; VRx-3996) is a Class I-selective oral hydroxamate histone deacetylase (HDAC) inhibitor active against HDAC 1-3, but not HDAC 6. N induces expression of EBV thymidine kinase (TK, BXLF1) and protein kinase (PK, BGLF4) in EBV+ lymphomas. This study examines if N+VG results in tumor sensitization to antivirals (i.e., VG) and impacts EBV-induced T-cell exhaustion. Methods: The study employs a 3+3 design with expansion in patients (pts) with relapsed/refractory EBV+ lymphomas (EBER-ISH). Objectives: Maximal Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D), and efficacy. Primary endpoint: safety. Secondary endpoints: PK, response rate. Exploratory endpoints: PBMC histone H3 acetylation (Ac), quantitative plasma EBV DNA (pEBVd), and immune biomarkers. Responses (investigator-assessed and centrally-reviewed) are based on the Lugano Classification. Early safety and efficacy data are reported. Results: As of 10-Jan-2019, 15 pts (4F/11M, median age 60 yrs [19-79]) were enrolled with a median of 2 prior therapies and various lymphoma subtypes. Cohort 1 (N 10 mg BID/VG 900 mg BID) exceeded MTD (DLTs: leukopenia, neutropenia and thrombocytopenia). PK demonstrated ~2-fold higher N exposure compared to a prior study. VG levels were consistent with published data. Doses were reduced in Cohort 2 (N 5 mg BID/VG 450 mg BID) with no DLTs to date and 3 active pts. Most non-hematologic treatment-related AEs (TRAEs) were G1-2. Most G3+ TRAEs were hematologic (neutropenia, leukopenia, thrombocytopenia). Increases in creatinine occurred early and responded to reductions in VG. Among 7 evaluable pts, 4 responses were seen (2 CR, 2 PR) in PTLD, DLBCL, AITL, and plasmablastic lymphoma. Two pts had SD, and 1 PD. Of 8 pts with detectable baseline pEBVd, 7 demonstrated a reduction (median -54% [17 to -83%]). PBMC H3 Ac levels, multi-cytokine expression panel, and functional assessments in CD8+ T cells are in progress. Conclusions: N+VG appears well-tolerated at 5 mg and 450 mg BID, respectively with hematologic DLTs in a higher dose cohort. Responses are observed at all doses in both B and T cell lymphomas, with reductions in pEBVd levels and changes in T cell functionality. A RP2D will be defined prior to dose expansion. Clinical trial information: NCT03397706.

We describe the asymmetric synthesis of actinoidic acid trimethyl ether with orthogonal protecting groups on the respective amino and carboxyl groups. The Stille biaryl coupling reaction of suitably functionalized aryl bromide and (trimethylstannyl)benzaldehyde gave the key intermediate biaryl aldehyde. Synthesis was accomplished by applying the asymmetric Strecker reaction to this aldehyde, followed by selectively removing the chiral auxiliary. By comparing its H-1-NMR spectra with those obtained from vancomycin, the stereochemistry of the synthesized diastereoisomer of actinoidic acid trimethyl ether was confirmed as an atropisomer of the (alpha S,alpha'R)-isomer.

Four new norditerpenes, taichunins A-D (1-4), were isolated from the fungus Aspergillus taichungensis (IBT 19404). Compound 1 has a new carbon framework. The absolute configurations were determined by the calculated ECD spectral method. Compound 1 was cytotoxic against HeLa cells with an IC50 value of 4.5 μM, whereas 2-4 were nontoxic at 50 μM.