Sponsor Perspectives on the Impact of the COVID-19 Pandemic on Interventional Cancer Clinical Trial Protocols and Data Quality.

PURPOSE: The onset of the COVID-19 pandemic created major disruptions in the conduct of cancer clinical trials. In response, regulators and sponsors allowed modifications to traditional trial processes to enable clinical research and care to continue. We systematically evaluated how these mitigation strategies affected data quality and overall trial conduct. METHODS: This study used surveys and live interviews. Forty-one major industry and National Cancer Institute Network groups (sponsors) overseeing anticancer treatment trials open in the United States from January 2015 to May 2022 were invited to participate. Descriptive statistics were used for survey data summaries. Key themes from interviews were identified. RESULTS: Twenty sponsors (48.8%; 15 industry and five Network groups) completed the survey; 11/20 (55.0%) participated in interviews. Sponsors predominantly (n = 12; 60.0%) reported large (≥11 trials) portfolios of phase II and/or phase III trials. The proportion of sponsors reporting a moderate (9) or substantial (8) increase in protocol deviations in the initial pandemic wave versus the pre-pandemic period was 89.5% (17/19); the proportion reporting a substantial increased dropped from 42.1% (n = 8/19) in the initial wave to 15.8% (n = 3/19) thereafter. The most commonly adopted mitigation strategies were remote distribution of oral anticancer therapies (70.0%), remote adverse event monitoring (65.0%), and remote consenting (65.0%). Most respondents (15/18; 83.3%) reported that the pandemic had minimal (n = 14) or no impact (n = 1) on overall data integrity. CONCLUSION: Despite nearly all sponsors observing a temporary increase in protocol deviations, most reported the pandemic had minimal/no impact on overall data integrity. The COVID-19 pandemic accelerated an emerging trend toward greater flexibility in trial conduct, with potential benefits of reduced burden on trial participants and sites and improved patient access to research.

Synthesis and crystal structure of bis-(2-phthal-imido-eth-yl)ammonium chloride dihydrate.

The title compound {systematic name: bis-[2-(1,3-dioxoisoindol-2-yl)eth-yl]aza-nium chloride dihydrate}, C20H18N3O4 +·Cl-·2H2O, is a phthalimide-protected polyamine that was synthesized by a previous method. It was characterized by ESI-MS, 1H NMR, and FT-IR. Crystals were grown from a solution of H2O and 0.1 M HCl. The central nitro-gen atom is protonated and forms hydrogen bonds with the chloride ion and a water mol-ecule. The two phthalimide units make a dihedral angle of 22.07 (3)°. The crystal packing features a hydrogen-bond network, two-coordinated chloride, and off-set π-π stacking.

The evolution of hydrated lime-based cementitious waste forms during leach testing leading to enhanced technetium retention.

The interaction between radionuclides and cementitious material phases is crucial in the prediction of the long-term disposal behavior of cementitious waste forms. This work focuses on the behavior of technetium-99 (Tc) within a hydrated-lime based waste form developed as a candidate to immobilize high-sulphate containing liquid wastes known to inhibit cement solidification when using a fly ash based formulation. In leach testing, the hydrated-lime based formulation demonstrated improvement in Tc retention over a fly ash containing formulation beginning after 14 d leaching. The mineralogical evolution of the hydrated-lime samples during leach testing showed a decrease in portlandite content and reduction capacity at the onset of the Tc retention improvement. Leach testing upwards of 400 days showed the improved Tc retention was sustained. Samples cured for different lengths of time (28 days vs 60 days) confirmed that the improved Tc retention and mineralogic change was caused by cement - leachant interactions and not the sample curing time. The Tc observed diffusivities in the hydrated-lime samples are amongst the lowest measured in a cement waste form tested for development at the US Department of Energy Hanford site, leading to a possible pathway to improved cement conditioning where contaminants can be retained for long disposal times.

Synthesis and structures of three benzoannelated macrobicyclic diamides.

We report the synthesis and structures of 9,10,20,21-tetrahydro-5,14-(ethanooxyethano)dibenzo[e,q][1,4,10,13,7,16]tetraoxadiazacyclooctadecine-6,13-dione [systematic name: 8,11,21,24,29-pentaoxa-1,18-diazatetracyclo[16.8.5.02,7.012,17]hentriaconta-2,4,6,12(17),13,15-hexaene-19,26-dione C24H28N2O8, I], 6,7,9,10,12,13,20,21-octahydro-5,14-(ethanooxyethano)dibenzo[e,q][1,4,10,13,7,16]tetraoxadiazacyclooctadecine-23,27-dione (8,11,21,24,29-pentaoxa-1,18-diazatetracyclo[16.8.5.02,7.012,17]hentriaconta-2,4,6,12,14,16-hexaene-27,31-dione; C24H28N2O7, II), and 9,10,20,21-tetrahydro-5,14-(ethanooxyethanooxyethano)dibenzo[e,q][1,4,10,13,7,16]tetraoxadiazacyclooctadecine-6,13-dione [8,11,21,24,29,32-hexaoxa-1,18-diazatetracyclo[16.8.8.02,7.012,17]tetratriaconta-2,4,6,12(17),13,15-hexaene-19,26-dione; C26H32N2O7, III]. All three compounds are made up of two tertiary diamides and are composed of two 15-membered rings with N2O3 donor sets and one 18-membered ring with an N2O4 donor set (compounds I and II) or three 18-membered rings with N2O4 donor sets (compound III). The solid-state structures of compounds I and II show little effects from the movement of the amide groups. However, compound III has a larger cavity and a different orientation of donor atoms in comparison to compounds I and II.

The behavior of iodine in stabilized granular activated carbon and silver mordenite in cementitious waste forms.

Both granular activated carbon (GAC) and silver mordenite (AgM) are utilized for the removal of contaminants and radionuclides (e.g., radioiodine) from off-gas streams in nuclear fuel reprocessing and high temperature immobilization of nuclear waste. Following their service lifetimes, the GAC and AgM contain an inventory of contaminants and radionuclides and require stabilization in a matrix for disposal. GAC and AgM are referred to as solid secondary waste (SSW) materials. Cementitious waste forms can be used as the stabilization matrix for SSW, however, for successful stabilization, the inclusion of GAC and AgM should not negatively impact the physical behavior of the cementitious waste form or increase release of the contaminants/radionuclides compared to the baseline case without stabilization. The present work focuses on evaluation of cement formulations, with and without slag, for the stabilization of iodine-loaded GAC or AgM. The results showed that both a slag-containing and slag-free formulations were able to stabilize GAC and AgM, up to 30 vol%, without deleterious impacts on the bulk physical properties of the encapsulating matrix. When monolithic samples of the GAC or AgM containing cement formulations were subjected to leach tests, it was observed that iodide leached from the SSW) had limited sorption to either of the cement matrices. Nonetheless, the iodine can interact with the SSW materials themselves. Specifically, iodine retention within monolithic samples containing the iodine-loaded GAC or AgM was improved for AgM containing waste forms while no improvement was observed for the GAC containing waste forms. The improvement for the AgM containing waste forms was likely due to an enrichment of Ag at the interface between the AgM particles and the cement matrix that can impede iodine migration out from the waste form. The results are significant in highlighting the potential for long-term retention of iodine in specific cementitious waste forms.

Crystal structure of 2,2'-{[(2-nitro-benz-yl)aza-nedi-yl]bis-(propane-3,1-di-yl)}bis-[1H-iso-indole-1,3(2H)-dione].

The structure of the title compound, C29H26N4O6, exhibits a folded conformation with the three arms all on the same side of the tertiary N atom. The two phthalimide units make a dihedral angle of 12.18 (12)° and the dihedral angles between the benzyl plane and the phthalimide units are 68.08 (7) and 67.71 (7)°. The crystal packing features π-π inter-actions.

Outpatient facility-based order variation in combined imaging.

OBJECTIVE: Combined computed tomography (CT) occurs when one anatomical area is simultaneously imaged both without and with contrast, or two overlapping anatomical areas are imaged concurrently. While this has been studied in a Traditional Medicare population, it has not been studied in other populations subject to prior authorization. This study explores between-facility variation in ordering and receiving orders to render combined CT in a mixed commercial and Medicare Advantage population. METHODS: Orders for CT abdomen (without/with contrast), CT thorax (without/with contrast), and concurrent CT brain and sinus authorized by a prior authorization company from 2013-2017, pertaining to patients with commercial or Medicare Advantage health plans from one national insurer, were extracted. Orders were issued and rendered by both hospitals and nonhospitals. The analysis was performed separately for each anatomical area in two ways: orders were grouped by ordering facility, and by designated rendering facility. For each facility, the ratio of combined to total orders was calculated, and analysis of variance was used to determine whether there were significant differences in this rate by year. The association between health plan type and combined imaging rates was assessed. RESULTS: Combined rates [ratio±standard deviation] for abdomen, thorax, and brain/sinus were 0.306±0.246, 0.089±0.142, and 0.002±0.01 respectively when the analysis was conducted according to ordering facility, and 0.311±0.178, 0.096±0.113, and 0.001±0.006 when the analysis was conducted according to designated rendering facility. Combined CT abdomen and CT thorax rates decreased monotonically from 2013 to 2017, decreases that were significant (P < .01) regardless of whether orders were grouped by ordering or rendering facility. Combined CT abdomen and CT thorax rates significantly differed between orders pertaining to people with commercial and Medicare Advantage plans. DISCUSSION: Variability was greater when orders were grouped by ordering facility, rather than rendering facility. Health plan type may influence whether a patient receives combined CT.

Radiopharmaceuticals for Relapsed or Refractory Ovarian Cancers.

Targeted radiopharmaceuticals for therapeutic use deliver radionuclides directly to tumor anywhere in the body, and therefore, have renewed interest for clinical development in women with disseminated chemorefractory ovarian cancers. About two in every five women with advanced stage ovarian cancer outlive their disease after the first treatment phase, with the rest rendered incurable due to the chemorefractory nature of their disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 67 phase I or phase Ib trials among women with relapsed or refractory ovarian cancer between 1989 and 2017 in an effort to uncover tolerable and effective drug combinations intended to increase survival rates. None of these early clinical development phase trials involved radiopharmaceuticals. Here, the NCI provides its perspective on targeted radiopharmaceutical conjugates alone or in combination with its experimental therapeutics portfolio for women with relapsed or refractory ovarian cancer. An infrastructure build for Federal radiopharmaceutical medical monitoring and adverse event reporting has begun.

Modification and Reinitiation of Lower Back Imaging Orders After Evidence-Based Collaborative Consultation.

RATIONALE AND OBJECTIVES: Practice guidelines suggest most patients should wait at least 28 days from the onset of low back pain before receiving imaging. This study evaluates a nondenial prior authorization program's performance in modifying lower back imaging orders. Ordering physicians were asked by a consulting physician to modify any order that did not meet guidelines through collaborative consultation. If original orders were not reinitiated, it could signify that modified orders met clinical objectives. MATERIALS AND METHODS: Prior authorization and claims data from 2014 to 2017 were analyzed to determine the rate of reinitiation within 28 days for modified computed tomography and magnetic resonance imaging orders. Chi-square tests were used to evaluate whether modification or reinitiation was associated with several factors. RESULTS: Across the four sequences of interaction between ordering physicians and the program examined, 533,768 orders were placed, leading to 6855 completed consultations (1.3% of orders), 1380 modifications (20.1% of consultations), and 224 reinitiations (16.2% of modifications). Modification led to reinitiation 7.1%-20.6% of the time, depending upon the sequence. Orders from primary care physicians were significantly more likely to be modified. Reinitiation was significantly more likely for urban orders. CONCLUSION: Low back imaging orders modified by the program were infrequently reinitiated within 28 days. Some reinitiation may have been consistent with evidence-based practice, as orders may have been placed after the onset of pain.

Prior Authorization for Elective Diagnostic Catheterization: The Value of Reviewers in Cases with Clinical Ambiguity.

BACKGROUND: In many situations, evidence-based guidelines cannot provide definitive guidance on the appropriateness of diagnostic catheterization. One specialty benefit management company has taken a 2-step approach to address this ambiguity by evaluating the appropriateness of diagnostic catheterization orders using a rule-based decision support system, and then having reviewers provide input through the consult system of a nondenial prior authorization program that involves peer discussion. OBJECTIVE: To describe the outcomes of a 2-step approach to evaluating the appropriateness of elective diagnostic catheterization orders. METHOD: This program evaluation used data from elective diagnostic catheterization orders from 2015 that pertained to 1 health insurer's Medicare Advantage plans. The classifications of orders by the rule-based system and the approval rates after review by the consult system are presented for these plans. Chi-square tests were conducted to examine whether classifications of the orders by the rule-based and consult systems were independent of plan type, specialty of the ordering physician, or state of residence of the patient. RESULTS: A total of 3808 orders for elective diagnostic catheterization in 2015 met the inclusion criteria. Inadequate initial justification was provided for 699 (18.4%) of the orders; after inquiry through the consult system, 509 (72.8%) of the remaining orders were approved. Among the 344 (9%) orders that were deemed potentially nonindicated according to the rule-based system, the consult system approved 298 (86.6%). Of the 2765 (72.6%) orders that were deemed potentially appropriate by the rule-based system, the consult system approved 2740 (99.1%). Chi-square tests did not show a significant association between plan type or physician specialty and the classification produced by the rule-based system or the consult system. The patients' state of residence was significantly associated with the classification of orders for the rule-based system (P <.001), but not for the consult system. CONCLUSION: Rule-based decision support can be combined with consult-based peer discussion to determine whether care is appropriate when guidelines are ambiguous. Poorly justified orders are often supportable after gathering information on the patient's presentation.

The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects.

PURPOSE: The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase I clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents. EXPERIMENTAL DESIGN: Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI's Organ Dysfunction Working Group's hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy's law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups. RESULTS: There were 513 and 1,328 subjects treated on HDCT (n = 9) and P1CT (n = 42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of alanine aminotransferase (ALT) in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy's law were met by 11 subjects on P1CT, but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT. CONCLUSIONS: The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials because baseline liver tests did not. Clin Cancer Res; 22(22); 5472-9. ©2016 AACR.

Do Case Rates Affect Physicians' Clinical Practice in Radiation Oncology?: An Observational Study.

Case rate payments combined with utilization monitoring may have the potential to improve the quality of care by reducing over and under-treatment. Thus, a national managed care organization introduced case rate payments at one multi-site radiation oncology provider while maintaining only fee-for-service payments at others. This study examined whether the introduction of the payment method had an effect on radiation fractions administered when compared to clinical guidelines. The number of fractions of radiation therapy delivered to patients with bone metastases, breast, lung, prostate, and skin cancer was assessed for concordance with clinical guidelines. The proportion of guideline-based care ascertained from the payer's claims database was compared before (2011) and after (2013) the payment method introduction using relative risks (RR). After the introduction of case rates, there were no significant changes in guideline-based care in breast, lung, and skin cancer; however, patients with bone metastases and prostate cancer were significantly more likely to have received guideline-based care (RR = 2.0 and 1.1, respectively, p<0.05). For the aggregate of all cancers, the under-treatment rate significantly declined (p = 0.008) from 4% to 0% after the introduction of case rate payments, while the over-treatment rate remained steady at 9%, with no significant change (p = 0.20). These findings suggest that the introduction of case rate payments did not adversely affect the rate of guideline-based care at the provider examined. Additional research is needed to isolate the effect of the payment model and assess implications in other populations.

Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities.

PURPOSE: Phase I studies rely on investigators to accurately attribute adverse events as related or unrelated to study drug. This information is ultimately used to help establish a safe dose. Attribution in the phase I setting has not been widely studied and assessing the accuracy of attribution is complicated by the lack of a gold standard. We examined dose-toxicity relationships as a function of attribution and toxicity category to evaluate for evidence of toxicity misattribution. EXPERIMENTAL DESIGN: Individual patient records from 38 phase I studies activated between 2000 and 2010 were used. Dose was defined as a percentage of maximum dose administered on each study. Relationships between dose and patient-level toxicity were explored graphically and with logistic regression. All P values were two-sided. RESULTS: 11,909 toxicities from 1,156 patients were analyzed. Unrelated toxicity was not associated with dose (P = 0.0920 for grade ≥ 3, P = 0.4194 for grade ≥ 1), whereas related toxicity increased with dose (P < 0.0001, both grade ≥ 3 and ≥ 1). Similar results were observed across toxicity categories. In the five-tier system, toxicities attributed as "possibly," "probably," or "definitely" related were associated with dose (all P < 0.0001), whereas toxicities attributed as "unlikely" or "unrelated" were not (all P > 0.1). CONCLUSIONS: Reassuringly, we did not observe an association between unrelated toxicity rate and dose, an association that could only have been explained by physician misattribution. Our findings also confirmed our expectation that related toxicity rate increases with dose. Our analysis supports simplifying attribution to a two-tier system by collapsing "possibly," "probably," and "definitely" related.

Comparison of metoprolol succinate versus carvedilol in time to cardiovascular admission in a Veterans Affairs healthcare system: An observational study.

OBJECTIVE: To determine if metoprolol succinate or carvedilol is more effective in delaying the time to first cardiovascular disease hospital admission in systolic heart failure patients. As a secondary objective, to determine the most effective dose of each agent in delaying first cardiovascular disease hospital admission, including but not limited to heart failure exacerbation, myocardial infarction, ischemic heart disease, cardiac arrhythmias, or death. METHODS: This study was a retrospective chart review of 272 veterans at the VA Boston Healthcare System newly started on metoprolol succinate (n = 157) or carvedilol (n = 115) between January 2000 and December 2008. After an 8-week study medication titration period, subjects were subcategorized into low-, medium-, and high-dose ranging groups and followed until the first cardiovascular disease hospitalization, death, or 365 days. The main outcome measure was time to first cardiovascular hospitalization or death. RESULTS: The mean age (69.9 years vs. 67.9 years) and ejection fraction (26% vs. 25%) were comparable between study arms at baseline. Mean time to first cardiovascular disease hospitalization was significantly different (p = 0.001) between study groups with 330.6 days with in metoprolol succinate group vs. 282.6 days in the carvedilol groups. High-dose carvedilol significantly delayed time to first hospitalization in comparison to medium or low carvedilol doses (p = 0.015, p = 0.005). Low- and high-dose metoprolol succinate were not significantly different (p = 0.509) in time to first event, and both dosing groups fared better compared to medium dose metoprolol succinate (p = 0.046). CONCLUSION: In this veteran patient population in need of additional heart failure treatments, metoprolol succinate use resulted in a delayed time to first cardiovascular disease hospitalization or death compared to carvedilol. Both low and high doses of metoprolol succinate showed a significant delay of time to first cardiovascular hospitalization compared to medium doses of metoprolol succinate. Higher doses of carvedilol showed a significant delay of time to cardiovascular hospitalization than lower carvedilol doses.

Nomogram to predict cycle-one serious drug-related toxicity in phase I oncology trials.

PURPOSE: All patients in phase I trials do not have equivalent susceptibility to serious drug-related toxicity (SDRT). Our goal was to develop a nomogram to predict the risk of cycle-one SDRT to better select appropriate patients for phase I trials. PATIENTS AND METHODS: The prospectively maintained database of patients with solid tumor enrolled onto Cancer Therapeutics Evaluation Program-sponsored phase I trials activated between 2000 and 2010 was used. SDRT was defined as a grade ≥ 4 hematologic or grade ≥ 3 nonhematologic toxicity attributed, at least possibly, to study drug(s). Logistic regression was used to test the association of candidate factors to cycle-one SDRT. A final model, or nomogram, was chosen based on both clinical and statistical significance and validated internally using a bootstrapping technique and externally in an independent data set. RESULTS: Data from 3,104 patients enrolled onto 127 trials were analyzed to build the nomogram. In a model with multiple covariates, Eastern Cooperative Oncology Group performance status, WBC count, creatinine clearance, albumin, AST, number of study drugs, biologic study drug (yes v no), and dose (relative to maximum administered) were significant predictors of cycle-one SDRT. All significant factors except dose were included in the final nomogram. The model was validated both internally (bootstrap-adjusted concordance index, 0.60) and externally (concordance index, 0.64). CONCLUSION: This nomogram can be used to accurately predict a patient's risk for SDRT at the time of enrollment. Excluding patients at high risk for SDRT should improve the safety and efficiency of phase I trials.

Similar efficacy for phase I trials in comparison with DTIC for advanced malignant melanoma: an analysis of melanoma outcomes in CTEP-sponsored phase I trials 1995-2011.

After ipilimumab, vemurafenib, and interleukin-2, standard of care chemotherapy for melanoma remains dacarbazine (response rate ∼9%). Despite this, many physicians hesitate to refer patients to phase I protocols given a perceived lack of clinical benefit and potential for harm. To better understand the validity of these perceptions, the experience of all patients with melanoma treated on phase I trials sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program (NCI-CTEP) from 1995 to 2011 were analyzed and compared with the pooled results of six contemporary phase III trials of dacarbazine. A total of 937 patients with melanoma were treated in 148 CTEP phase I trials. The majority were men with a median of two prior therapies (46% receiving prior dacarbazine). Response and clinical benefit rates in these trials were not clinically different from those of dacarbazine (phase I: 6.3 and 26.8% vs. dacarbazine: 8.8 and 27.9%) although grades 3 and 4 toxicity was significantly higher (54 vs. 28%). Efficacy and toxicity were generally consistent within phase I subgroups (targeted agents, immunotherapies, or chemotherapeutics) though targeted therapy was associated with a lower response rate, immunotherapy with lower clinical benefit rate, and chemotherapy with higher incidence of grade 4 toxicity. Thus, the perception of limited efficacy of phase I trials for patients with melanoma was disproven, whereas the perception of toxicity was observed. However, this difference in toxicity may have been largely because of the nature of phase I vs. phase III trials (i.e. more heavily pretreated) and because of the phase I trials often being multiagent as opposed to dacarbazine alone.

Are women with functional limitations at high risk of underutilization of mammography screening?

OBJECTIVES: Women with functional limitations face obstacles in adhering to established mammography guidelines owing to personal factors and barriers within the health care system. Whereas some studies have focused on either physical or cognitive limitations that correlate with lower rates of cancer screening, this study examined multiple functional limitations (physical, psychological, and sociability) and mammography screening. METHODS: Data from the 2000 National Health Interview Survey were analyzed for 9,505 women aged > or =40 years. We hypothesized that women with functional limitations (physical, psychological, and/or sociability) are less likely to receive screening mammography. Access variables (insurance coverage and usual source of health care) and utilization variables (physician contact and receipt of clinical breast examination) were included. Using multiple logistic regression (MLR), we estimated the relative contribution of functional limitations on mammography use after accounting for sociodemographic characteristics and confounding variables. RESULTS: An estimated 34.6% of women had physical limitations, 16.1% sociability limitations, and 8.1% psychological limitations. After controlling for all other variables, MLR analysis indicated that women with moderate or severe sociability limitations were less likely than their unimpaired counterparts to utilize mammography (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.48-0.81). Interestingly, women with severe physical limitations were more likely than physically able women to utilize mammography screening (OR, 1.28; 95% CI, 1.07-1.53). Women with no insurance, no usual care, and no doctor's visit within the past year were substantially less likely to use mammography screening. CONCLUSIONS: Sociability limitations, lack of access to health care, and limited regular checkups played significant roles in underutilization of screening mammography.

1,15:21,35-Bis(oxydiethyl-ene)-5,8,11,18,25,28,31,38-octa-oxa-1,15,21,35-tetra-azacyclo-tetra-decane-16,20,36,40-tetra-one-benzene (1/2): a macrotricyclic tetra-lactam.

The macrotricyclic title compound, C(36)H(64)N(4)O(14)·2C(6)H(6), is located on a crystallographic center of symmetry. The mol-ecule has four tertiary amide bridgehead atoms and consists of two unsymmetrical 20-membered diaza-tetra-oxamacrocycles (N(2)O(4) donor atom set) connected through the N atoms by two lateral oxydiethyl-ene bridges. The bridging subunits, together with the short bridging strand (NCCOCCN) from each monocycle, define a 24-membered ring (N(4)O(4) donor atom set) that forms a central cavity.

6,7,9,10-Tetra-hydro-16,22-ethano-oxyethano-5,8,11,19-tetra-oxa-16,22-diaza-dibenzo[h,q]cyclo-octa-decine-17,21-dione: a benzyl-annelated macrobicyclic diamide.

The macrobicyclic title compound, C(24)H(28)N(2)O(7), has two tertiary diamide bridgehead atoms and is composed of a 12-membered ring (N(2)O(2) donor set) and two 18-membered rings (N(2)O(4) donor sets). The solid-state structure shows that each of the amide groups is not coplanar with the adjacent benzene ring and NMR studies indicate that this conformational relationship persists in solution.

Three related benzoannelated diazapolyether macrocycles: effects of macrocycle ring size and position of benzo groups on hydrogen bonding of the amine H atoms.

The benzoannelated diazapolyether macrocycles 6,7,9,10,17,18-hexahydro-5H,11H-8,16,19-trioxa-5,11-diazadibenzo[a,g]cyclopentadecene, C(18)H(22)N(2)O(3), (I), 6,7,9,10,12,13,20,21-octahydro-5H,14H-8,11,19,22-tetraoxa-5,14-diazadibenzo[a,g]cyclooctadecene, C(20)H(26)N(2)O(4), (II), and 6,7,9,10,17,18,20,21-octahydro-16H,22H-5,8,11,19-tetraoxa-16,22-diazadibenzo[a,j]cyclooctadecene 0.3-hydrate, C(20)H(26)N(2)O(4) x 0.304H(2)O, (III), show different patterns of hydrogen bonding. In (I), the amine H atoms participate only in intramolecular hydrogen bonds with ether O atoms. In (II), the amine H atoms form intramolecular hydrogen bonds with the phenoxy ether O atoms and intermolecular hydrogen bonds with alkyl ether O atoms in an adjacent molecule, forming a chain linking the macrocycles together via an R(2)(2)(10) motif. Molecules of (II) were found on a crystallographic twofold axis. In (III), the amine H atoms participate in a hydrogen-bond network with adjacent ether O atoms and with a water molecule [having a partial occupancy of 0.304 (6)] that links the molecules together via a C(2)(2)(7) motif.