AiZynth impact on medicinal chemistry practice at AstraZeneca.

AstraZeneca chemists have been using the AI retrosynthesis tool AiZynth for three years. In this article, we present seven examples of how medicinal chemists using AiZynth positively impacted their drug discovery programmes. These programmes run the gamut from early-stage hit confirmation to late-stage route optimisation efforts. We also discuss the different use cases for which AI retrosynthesis tools are best suited.

Investigation of TG-43 Dosimetric Parameters for 192Ir Brachytherapy Source Using GATE Monte Carlo Code.

Purpose: According to the revised Task Group number 43 recommendations, a brachytherapy source must be validated against a similar or identical source before its clinical application. The purpose of this investigation is to verify the dosimetric data of the high dose rate (HDR) BEBIG 192Ir source (Ir2.A85-2). Materials and Methods: The HDR 192Ir encapsulated seed was simulated and its main dosimetric data were calculated using Geant4 Application for Tomographic Emission (GATE) simulation code. Cubic cells were used for the calculation of dose rate constant and radial dose function while for anisotropy function ring cells were used. DoseActors were simulated and attached to the respective cells to obtain the required data. Results: The dose rate constant was obtained as 1.098 ± 0.003 cGy.h - 1.U - 1, differing by 1.0% from the reference value reported by Granero et al. Similarly, the calculated values for radial dose and anisotropy functions presented good agreement with the results obtained by Granero et al. Conclusion: The results of this study suggest that the GATE Monte Carlo code is a valid toolkit for benchmarking brachytherapy sources and can be used for brachytherapy simulation-based studies and verification of brachytherapy treatment planning systems.

Accurate modeling and performance evaluation of a total-body pet scanner using Monte Carlo simulations.

BACKGROUND: The limited axial field-of-view (FOV) of conventional clinical positron emission tomography (PET) scanners (∼15 to 26 cm) allows detecting only 1% of all coincidence photons, hence limiting significantly their sensitivity. To overcome this limitation, the EXPLORER consortium developed the world's first total-body PET/CT scanner that significantly increased the sensitivity, thus enabling to decrease the scan duration or injected dose. PURPOSE: The purpose of this study is to perform and validate Monte Carlo simulations of the uEXPLORER PET scanner, which can be used to devise novel conceptual designs and geometrical configurations through obtaining features that are difficult to obtain experimentally. METHODS: The total-body uEXPLORER PET scanner was modeled using GATE Monte Carlo (MC) platform. The model was validated through comparison with experimental measurements of various performance parameters, including spatial resolution, sensitivity, count rate performance, and image quality, according to NEMA-NU2 2018 standards. Furthermore, the effects of the time coincidence window and maximum ring difference on the count rate and noise equivalent count rate (NECR) were evaluated. RESULTS: Overall, the validation study showed that there was a good agreement between the simulation and experimental results. The differences between the simulated and experimental total sensitivity for the NEMA and extended phantoms at the center of the FOV were 2.3% and 0.0%, respectively. The difference in peak NECR was 9.9% for the NEMA phantom and 1.0% for the extended phantom. The average bias between the simulated and experimental results of the full-width-at-half maximum (FWHM) for six different positions and three directions was 0.12 mm. The simulations showed that using a variable coincidence time window based on the maximum ring difference can reduce the effect of random coincidences and improve the NECR compared to a constant time coincidence window. The NECR corresponding to 252-ring difference was 2.11 Mcps, which is larger than the NECR corresponding to 336-ring difference (2.04 Mcps). CONCLUSION: The developed MC model of the uEXPLORER PET scanner was validated against experimental measurements and can be used for further assessment and design optimization of the scanner.

Assessment of combined modality therapy for non-small-cell lung carcinoma: A simulation study concerning concurrent chemo-brachytherapy.

Although surgery is the treatment of choice for early-stage non-small-cell lung carcinoma, almost two-thirds of patients do not have acceptable pulmonary function for extensive surgeries. The alternative approach for this large group of patients is sublobar resection along with low-dose-rate (LDR) brachytherapy (BT). However, patients with resected lungs have a high risk of recurrence and are often treated with platinum-based (Pt-based) chemotherapy (CT). In this study, we aimed to evaluate the absorbed doses of lung and other thoracic organs, considering concurrent chemo-BT with LDR sources in two modalities: conventional vs. unconventional Pt-based CT. We used the MCNPX code for simulations and to obtain the lung absorbed dose, dose enhancement factor (DEF), and Pt threshold concentration for the abovementioned modalities. Our results indicate that DEF correlates directly with Pt concentration at prescription point and is inversely correlated with depth. Dose enhancement for conventional CT concurrent with BT is <2%, while it is >2% in case of unconventional Pt-based CT wherein the Pt concentration exceeds 0.2 mg/g lung tissue. Also, the absorbed dose of healthy thoracic organs decreased by 2-11% in the latter approach. In conclusion, the concurrent chemo-BT in the lung environment could enhance the therapeutic doses merely by using unconventional CT methods, while lung Pt accumulation exceeds 0.2 mg/g.

A Case of COVID-19 Vaccine-Induced Thrombotic Thrombocytopenia.

This report discusses a case of a 37-year-old female who developed vaccine-induced thrombotic thrombocytopenia (VITT) after receiving the Johnson and Johnson COVID-19 vaccination. The patient first presented to the ED with complaints of a worsening headache. Labs were significant for thrombocytopenia with a platelet count of 22,000, and the patient was admitted to the inpatient unit for monitoring. The day after admission, the patient was found to have a right common femoral artery embolus, left distal popliteal trifurcation embolism, a small pulmonary embolism in the right lower lobe, and a mural thrombus of the infrarenal abdominal aorta. Following these findings, the patient underwent emergent thrombectomy of the common and superficial femoral arteries. Over the hospital course of six days, the patient received steroids and IV immunoglobulin (IVIG), which led to the resolution of the thrombocytopenia. The patient was given argatroban followed by apixaban for anticoagulation. She was instructed to follow up with hematology within one to two weeks post-discharge for monitoring of anticoagulation and thrombus surveillance. This case report outlines the clinical course, diagnosis, and treatment of a case of VITT, which will assist physicians in early recognition and adequate treatment of this condition as the COVID-19 pandemic continues.

Super-selective intra-arterial platinum-based chemotherapy concurrent with low-dose-rate plaque brachytherapy in the treatment of retinoblastoma: A simulation study.

OBJECTIVE: Retinoblastoma is the most common cancer among children under 5 years of age. The common conventional methods for the treatment of retinoblastoma include chemotherapy and brachytherapy (BT). This study investigated the concurrent use of BT with 125I and 103Pd sources and chemotherapy with platinum-based chemotherapy drugs for retinoblastoma. MATERIALS AND METHODS: The absorbed doses in different parts of the eye were measured with and without platinum. Platinum concentrations of 5, 7.5, 10, and 15 mg/g were evaluated, and the dose enhancement factors (DEFs) were calculated for different cases. RESULTS: For the 125I source, the DEFs at the tumor apex were 1.49, 1.67, 1.81, and 1.97 at concentrations of 5, 7.5, 10, and 15 mg/g, respectively. The DEF decreased dramatically beyond the apex at 0.85 cm from tumor base and was 0.87, 0.82, 0.76, and 0.63 for the abovementioned concentrations, respectively. For the 103Pd source, the DEFs were 1.15, 1.24, 1.21, and 1.07, respectively, at the apex and 0.76, 0.65, 0.56, and 0.39, respectively, beyond the apex. CONCLUSIONS: Our results showed that the concurrent use of low-dose-rate plaque BT and platinum-based chemotherapy significantly increased the tumor-absorbed dose and decreased the absorbed dose in areas outside the tumor and the treatment time.

Effect of Rivastigmine (Acetyl Cholinesterase Inhibitor) versus Placebo on Manic Episodes in Patients with Bipolar Disorders: Results from a Double Blind, Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: To treat patients with bipolar disorders (BPD) during the acute phase, the standard procedure is to administer lithium or sodium valproate. To further optimize treatment, acetylcholinesterase inhibitors such as donepezil and galantamine have gained increased interest, though with conflicting results. In the present randomized, double-blind, placebo-controlled clinical trial, we investigated whether, and to what extent, adjuvant rivastigmine might improve symptoms of mania in patients with BPD during the acute manic phase. METHODS: A total of 70 patients with BPD in an acute state of mania (mean age 33.8 years; 24% females) took part in this study. After a thorough clinical interview, standard treatment consisted of 20mg/kg/day of sodium valproate; next, patients were randomly assigned either to the adjuvant rivastigmine or to the placebo condition. The study duration was 24 days. The dose of rivastigmine was 1.5 mg for the first 7 days and 3 mg from day 8 to day 24. Experts blind to the patients' study condition rated patients' mania scores, symptom severity, and symptom improvements at baseline (except symptom improvements) and 4, 8, 12, and 24 days after the beginning of this study. RESULTS: Symptoms of mania improved over time, but more so in the adjuvant rivastigmine compared to the placebo condition. Greater improvements were observed from day 8 on. CONCLUSIONS: The pattern of results from the present randomized, placebo-controlled, double-blind study suggests that adjuvant rivastigmine, a cholinesterase inhibitor, improved symptoms of mania among a larger sample of inpatients with BPD and in the acute manic state. However, the improvements were modest, and the results should be replicated and above all balanced against side effects.

The diagnostic accuracy of endobronchial ultrasound and spiral chest computed tomography scan in the prediction of infiltrating and non-infiltrating lymph nodes in patients undergoing endobronchial ultrasound.

PURPOSE: Endobronchial ultrasound (EBUS) and spiral chest computed tomography (CT) scan are important methods in the prediction of infiltrating and non-infiltrating lymph nodes, and the determination of their diagnostic accuracy would result in a reduction of the burden of problems and an improvement in prognosis. The purpose in this study was to determine the diagnostic accuracy of endobronchial ultrasound and spiral chest CT scan in the prediction of infiltrating and non-infiltrating lymph nodes in patients undergoing endobronchial ultrasound. MATERIAL AND METHODS: In this observational prospective study, 40 consecutive patients with infiltrating and non-infiltrating lymph nodes in Masih-Daneshvari Hospital in 2017 and 2018 were enrolled, and the sensitivity, specificity, and accuracy of EBUS and CT-scan versus fine needle aspiration pathology results were determined in them. RESULTS: The results in this study demonstrated that the congruence between EBUS and CT scan was 80.5% (p = 0.0001). The sensitivity, specificity, and accuracy for CT scan were 100%, 22.6%, and 40%, respectively, and the sensitivity, specificity, and accuracy for EBUS were 100%, 16.1%, and 35%, respectively. CONCLUSION: According to the obtained results, it may be concluded that CT scan and EBUS results have good congruence and high sensitivity to differentiate infiltrating and non-infiltrating lymph nodes. Hence, these methods are useful for screening methods, but due to their low specificity and accuracy the use of them for a confirmative approach is not beneficial. However, regarding the accessibility and less invasive nature, use of chest CT scan is more rational and is recommended in these patients.

Occupational doses of cardiologists in cath labs and simulation method.

In recent years, using the ionizing radiation in the interventional cardiology has been increased; this is because of the rapid growth of the number of interventional procedures and the high levels of radiation dose in these examinations. Therefore, it is necessary to develop procedures for managing the use of fluoroscopy radiation to ensure that patients and personnel are not exposed to excessive levels of radiation. It seems that by the new generation devices of fluoroscopy that are equipped with a real dosimeters or dose area product (DAP)-meter which are able to record the produced dose rate in the area of patient's body in each procedure, it is possible to calculate the cardiologist dose with simulation. In addition, a relationship can be made between the patient DAP and cardiologist dose that is defined as an appropriate conversion factor. Hence, in each procedure, besides the record of patient's DAP, the cardiologist dose is recorded as well.

Mathematical formulation of 125I seed dosimetry parameters and heterogeneity correction in lung permanent implant brachytherapy.

OBJECTIVES: Precise determination of dose distribution around low-energy brachytherapy sources as well as considering tissue heterogeneity is crucial for optimized treatment planning. This study is aimed at determination and mathematically formulation of American Association of Physicists in Medicine Task Group No. 43 (AAPM TG-43) dosimetry parameters of 125I seed (model 6711) and calculation of dose difference caused by neglecting lung heterogeneity in permanent implant brachytherapy. MATERIALS AND METHODS: Using MCNPX 2.6.0 code, 125I seed (model 6711) was simulated in a cubic water environment, and its dosimetry parameters mentioned in AAPM TG-43 protocol were obtained. After benchmarking of parameters and comparison with prior studies, mathematical equations were fitted to the data, and a specific set of 125I seeds was simulated on a plane in simulated lung and water environments. Appropriate photon histories were considered to achieve data with maximum accuracy (max error 1%). In the end, isodose curves, profiles, depth dose, and dose difference between lung and water environments were obtained. RESULTS: For 125I seed (model 6711), radial dose function and anisotropy functions were obtained precisely with R2 > 0.99, all in good agreement with previous studies and protocol. In addition, percentage dose difference between inhomogeneous lung and homogenous water environments in a 5 cm distance was calculated and presented as D (r) function with R2 > 0.99. CONCLUSIONS: Considering practical difficulties in dose calculations, 125I seed dosimetry parameters and lung heterogeneity corrections can be obtained precisely by MCNPX. Equations presented in this study are recommended to be considered in future studies based on lung permanent implantation.

Epigallocatechin-3-gallate promotes apoptosis in human breast cancer T47D cells through down-regulation of PI3K/AKT and Telomerase.

BACKGROUND: Green tea has antioxidant, anti-tumor and anti-bacterial properties. Epigallocatechin-3-gallate (EGCG) in green tea is highly active as a cancer chemopreventive agent. In this study, we designed a series of experiments to examine the effects of EGCG on proliferation and apoptosis of estrogen receptor α-positive breast cancer (T47D) cells. METHODS: Cells were treated with EGCG (0-80µM) and tamoxifen (0-20µM), as the positive control, up to 72h. Cell viability was determined by MTT assay. Apoptosis investigated by real time PCR of apoptosis and survival (Bax, Bcl-2, p21, p53, PTEN, PI3K, AKT, caspase3 and caspase9 and hTERT) genes and by western blot of Bax/Bcl-2 proteins expressions. RESULTS: The results showed that EGCG decreased cell viability as concentration- and time-dependently. IC50 values were 14.17µM for T47D and 193.10µM for HFF cells, as compared with 3.39µM and 32.75µM for tamoxifen after 72h treatment, respectively. Also, EGCG (80µM) significantly increased the genes of PTEN, CASP3, CASP9 and decreased AKT approximately equal to tamoxifen. In gene expression, EGCG (80µM) significantly increased Bax/Bcl-2 ratio to 8-fold vise 15-fold in tamoxifen (20µM)-treated T47D cells during 72h. In protein expression of Bax/Bcl-2, EGCG significantly increased 6-fold while this ratio augmented 10-fold in tamoxifen group. EGCG significantly decreased 0.8, 0.4 and 0.3 gene expression of hTERT in 24, 48 and 72h, respectively. CONCLUSIONS: This study suggests that EGCG may be a useful adjuvant therapeutic agent for the treatment of breast cancer.

Evaluation of dose enhancement in presence of gold nanoparticles in eye brachytherapy by 103Pd source.

In recent years, the use of gold nanoparticles in radiation therapy has been introduced as a new approach in radiotherapy. The aim of this study is to investigate the effect of gold nanoparticles (GNPs) in plaque brachytherapy for choroidal melanoma using Monte Carlo (MC) simulation. MCNPX code was used for simulation of human eye, 103Pd (model 200) brachytherapy source and the 20 mm COMS eye plaque that was loaded with 24 103Pd seeds and standardized by Collaborative Ocular Melanoma Study (COMS). The tumour was defined from the inner surface of choroid with 0.55 cm height and latticed with gold nanospheres and it was filled with different concentrations of 5, 10 and 15 mg/g GNPs, separately. Dose rate and dose enhancement factor in tumour and normal tissues of the eye (without gold) was examined for this case and compared with gold-water mixture of the same concentrations distributed in the tumour. The results show that with increasing the concentration of GNPs, the dose in the tumour increases and the dose to the normal tissues decreases. Furthermore, the time that is required to deliver the prescribed dose to the tumour decreases. In the gold nanosphere case for 5, 10 and 15 mg/g concentrations, the DEF in the apex of the tumour are 1.28, 1.46, 1.44 and at the distance of 6.5 mm in the normal tissue (outside the tumour) this factor would be 0.82, 0.73 and 0.68. The comparison between two cases of gold nanospheres and gold-water mixture shows that when the gold concentrations are defined as mixed with water, the dose enhancement in the first depths are higher than when the gold-nanoparticles are distributed inside the tumour. Furthermore due to more reduced particle flux for water-mixture case, by an increase in the depth the dose enhancement in gold-nanosphere increases compared with gold-water mixture case.

Prevalence of anti-Neospora caninum antibodies in Iranian goats.

UNLABELLED: Many species of animals play the role of intermediate host for Neospora caninum. Although the neosporosis has a global distribution, however there is no information on goats' infection in Iran. The main goal of present study was to determine the seroprevalence of N. caninum in goats of western Iran. A total of 450 sera were taken and analyzed for antibodies to N. caninum using ELISA technique. Of those, 28 (6.2%) examined goats were found to be seropositive (95%, CI=6.2±2.2%). In which male goats (11.1%) had the highest IgG against N. caninum with more than 2 years-old (54.4%). There was significant difference between prevalence and age. Positive association were in animals with history of abortion (18/30, 60%) and IgG against N. caninum. No correlations were found between male and female. This was the first report on N. caninum infection in Iranian goats and may be responsible for abortion and economic losses in goat husbandry in the region. KEY WORDS: goat, Neospora caninum, ELISA, Iran.

A survey on Sarcocystis spp. infection in cattle of Tabriz city, Iran.

Sarcocystis is one of the most prevalent protozoan parasites in the striated muscles of livestock slaughtered for food such as cattle, sheep and goat. Meat that is heavily infected may be condemned as unfit for human consumption. The aim of this study was to determine the prevalence of Sarcocystis spp. in slaughtered cattle in Tabriz, northwest of Iran. The prevalence of Sarcocystis spp. infection was investigated in 670 cattle, slaughtered from April 2013 to October 2013 in the Tabriz abattoir, Iran using naked eye examination for macroscopic Sarcocysts, and peptic digestion, muscle squash, squeezing methods for microscopic types. Muscles from oesophagus, tongue, heart, diaphragm and cervical and abdominal of 670 slaughtered cattle were examined for Sarcocystis spp. cysts. The prevalence of microscopic Sarcocystis spp. cysts in cattle was detected in 100 % and there was detected in macroscopic cyst 8.2 % in examined cattle. There were no significant differences among the infection rates of the different organs (P > 0.05). There were no significant differences among the infection rates of the different ages (P > 0.05). The prevalence of macroscopic infection in the oesophagus was higher than that of the other organs (P < 0.05). The infection rate was independent of sex (8.25 % in males and 8.13 % in females, P > 0.05). This suggests that meat should be cooked sufficiently, since a macroscopic inspection may not provide true results. Also, it has of great importance the farmers to be trained not to feed their dogs and cats with uncooked meat, and the abattoir remnants to be burned, in order to be effectively broken of infection cycle between the intermediate and the definitive hosts in Tabriz city, northwest of Iran.

The role of sheep in the epidemiology of Sarcocystis spp. in Tabriz area northwest of Iran.

The parasites of genus Sarcocystis are among the most commonly found parasites in domestic ruminants and some species of Sarcocystis can generate important economic loss when causing clinical and subclinical disease. In the present study, three techniques-direct inspection, impression smears and digestion method-were used for the diagnosis of Sarcocystis infection in 130 slaughtered sheep in Tabriz abattoir from April 2013 to October 2013. A total of 620 slaughtered sheep were selected randomly and their oesophagus and diaphragm were inspected using naked eye examination. In the second stage, 130 carcasses out of the 620 which had no apparent infection were selected randomly and their meat investigated using two techniques: impression smear with staining and pepsin digestion. The percentage of macroscopic cysts found in the oesophagus and diaphragm muscle was 5.64 and 2.74 %, respectively, and microscopically, infection was found in 100 % of the organs. There was no significant difference between different ages or between males and females. Although all of the sheep were found to be infected with Sarcocystis, majority of the cysts were demonstrated microscopically. This suggests that meat should be cooked sufficiently, since a macroscopic inspection may not provide true results. Also, it has of grea t importance the farmers to be trained not to feed their dogs and cats with uncooked meat, and the abattoir remnants to be burned, in order to be effectively broken of infection cycle between the intermediate and the definitive hosts in Tabriz city, northwest of Iran.

Survey of hydatidosis infection in slaughtered camel (Camelus dromedarius) in Tabriz area, Northwest Iran.

Hydatid Disease is the name given to the condition caused by the zoonotic tapeworm Echinococcus granulosus. The tapeworm spends most of its adult life in the intestine of its definitive host, namely canids and in particular the dog. The tapeworm eggs become voided in the canids' faeces and as a result of ingesting the eggs, infection passes to the intermediate host, commonly herbivores while grazing. However, humans can become accidentally infected and hydatid cysts may develop throughout the body. During April 2010-February 2014, a total 198 camels, which had been sent to the abattoir, the daily number of hydatid infected livers and lungs of camels slaughtered at Tabriz abattoir were recorded. To be sure about the validity of recorded data, observed data were collected daily. Approximately 29 (14.64 %) of camels were infected according to this survey. Age wise, the prevalence of infection in young animals (under the age of 5 years) was 4 (2.02 %), whereas in animals between 5 and 10 years and over, the prevalence of infection was 11 (5.55 %) and 14 (7.07 %) respectively. Sex wise, female animals had a higher prevalence with 17 (19.76 %) cases in camels, whereas in the males, there were 12 (10.71 %) cases in camels. There was a notable difference found in our study between male and female animals (P < 0.05). Infections were recorded in two visceral organs with the Lungs having the highest prevalence in camels, and the liver had low infected in camels. The results of this study suggest that infection of camels with hydatid cyst is common in Tabriz, Iran and that this may constitute economic and health problems in the meat industry.

Prevalence of Infection with the Larval Form of the Cestode Parasite Taenia saginata in Cattle in Northwest Iran and its Zoonotic Importance.

OBJECTIVE: Bovine cysticercosis is a cattle infection caused by a tapeworm, Taenia saginata. While the condition is relatively innocuous, the parasite infects the small intestine of humans in its mature stage and causes a few specific symptoms such as abdominal pain and nausea. METHODS: Between February 2013 and February 2014, a total of 640 cattle were randomly selected from all the cattle sent to the abattoir, and some internal organs and skeletal muscles of these cattle were inspected. RESULTS: Overall, 11 (1.71%) cattle were infected with the larval form of the cestode parasite T. saginata. In addition, the infection was more prevalent in cattle aged above 12 months than in those aged below 12 months [10 (2.06%) vs. 1 (0.64%)]. The prevalence of infection was significantly higher in female animals [8 (3.72%)] than in male animals [3 (0.70%)] (p<0.05). However, no significant difference was found between the rates in the 2 age groups or in different seasons. While the infections were detected in several visceral organs, no significant difference was found between their infection rates. CONCLUSION: The comparatively high prevalence of Cysticercus bovis infection in the cattle in Tabriz, Iran, may contribute to economic and health problems in the country's meat industry. On the other hand, the role of public health education in C. bovis infection control cannot be neglected.

Sleep patterns and habits in high school students in Iran.

BACKGROUND: Sleep patterns and habits in high school students in Iran have not been well studied to date. This paper aims to re-address this balance and analyse sleep patterns and habits in Iranian children of high school age. METHODS: The subjects were 1,420 high school students randomly selected by stratified cluster sampling. This was a self-report study using a questionnaire which included items about usual sleep/wake behaviours over the previous month, such as sleep schedule, falling asleep in class, difficulty falling asleep, tiredness or sleepiness during the day, difficulty getting up in the morning, nightmares, and taking sleeping pills. RESULTS: The mean duration of night sleep was 7.7 h, with no difference between girls, boys, and school year (grade). The mean time of waking in the morning was not different between genders. About 9.9% of the girls and 4.6% of the boys perceived their quality of sleep as being bad, and 58% of them reported sleepiness during the day. About 4.2% of the subjects had used medication to enhance sleep. The time of going to bed was associated with grade level and gender. Sleep latency was not associated with gender and grade level, l and 1.4% experienced bruxism more than four times a week. CONCLUSION: Our results are in contrast with that of previous studies that concluded sleep duration is shorter in Asia than in Europe, that boys woke-up significantly later than girls, and that the frequency of sleep latency category was associated with gender and grade level. The magnitude of the daytime sleepiness, daytime sleepiness during classes, sleep latency, and incidences of waking up at night represent major public health concerns for Iran.

Inter- and intramolecular [4 + 1]-cycloadditions between electron-poor dienes and electron-rich carbenes.

Inter- and intramolecular [4 + 1]-annulations between dialkoxy carbenes and electron-deficient dienes afford mono- or bicyclic products in moderate to good yield.

Characteristics of the two frontier orbital interactions in the Diels-Alder cycloaddition.

Two electron-deficient dienes were reacted with a series of twelve electron-poor and electron-rich dienophiles to give, in some cases, the corresponding Diels-Alder adducts. Clear differences in the roles played by the two frontier orbital interactions emerged. It was demonstrated that in the case of normal Diels-Alder cycloadditions, the FMO theory could predict the relative reactivities between dienophiles, while in the case of inverse-electron demand Diels-Alder reactions, it could not. It was shown that the dissymmetry in electron-rich dienophiles increases their reactivities.