Syntheses of naturally occurring cytotoxic [7.7]paracyclophanes, (-)-cylindrocyclophane A and its enantiomer, and implications for biological activity.

The total syntheses of (-)-cylindrocyclophane A (1), a naturally occurring, cytotoxic [7.7]paracyclophane, and its enantiomer have been achieved in an enantiodivergent manner starting from a chiral propargyl alcohol building block using Smith's cross metathesis/ring-closing metathesis protocol as the key step. The biological evaluation of both enantiomers of cylindrocyclophane A (1 and ent-1) and its analogues indicated that the chirality of 1 is irrelevant to its cytotoxicity, which is attributed to the resorcinol motifs embedded in the robust [7.7]paracyclophane framework.

Bidi smoking and lung cancer incidence among males in Karunagappally cohort in Kerala, India.

The association of lung cancer incidence with bidi smoking was examined using a cohort study data in Karunagappally, Kerala, India. We sought interview of all the residents in Karunagappally with the population of 385,103 in 1991 census, and established a cohort of 359,619 (93% of the population in 1991) in the 1990s. There were 65,829 men aged 30-84 at interview after excluding those diagnosed as cancer or died of any cause before 1997. Among them, 212 newly diagnosed lung cancer cases were ascertained during the 8-year period between 1997 and 2004 through Karunagappally Cancer Registry. The relative risk (RR) of lung cancer was obtained from Poisson regression analysis of grouped data. Lung cancer incidence was relatively high among Moslem people and those with lower educational history. When taking into account attained age, religion and education, the RR between current bidi smokers and those who had never smoked bidis was 3.9 (95%CI = 2.6-6.0, p < 0.001). The lung cancer risk did not return to the level of non-smokers within 10 years after cessation. In further analyses using only those never smoked cigarettes to examine the effect of bidi smoking alone on lung cancer risk, current smokers of bidis had the RR of 4.6 (95%CI = 2.5-8.5, p < 0.001). Lung cancer incidence increased with larger amounts of bidi smoked a day (p < 0.001), with longer durations of smoking bidis (p < 0.001), and with younger ages starting smoking bidis (p < 0.001). Immediate measures should be taken to stop bidi smoking, which is common in south Asia.

Dose limits below which the effect of radiation on health becomes undetectable due to background variation.

To clarify the low-dose limit at which the effect of radiation on health becomes undetectable is important in the regulation of radiation. As one of a series of cytogenetical studies on the effect of radiation on health, we present low-dose limits determined by analyzing the background frequencies of translocations in the lymphocytes of people living in normal circumstances. The frequencies of translocations in the lymphocytes were analyzed in 20 non-smokers (61.2-year-old on the average) in a large city, and 16 non-smokers (64.4-year-old on the average) and 8 children (12.3-year-old on the average) in a remote village. The radiation dose was calculated based on the background frequencies of translocations assuming that all the translocations had been induced by radiation. The calculated doses were 384+/-200, 336+/-124 and 128+/-80 mSv in the case of chronic exposure, and 248+/-153, 225+/-104 and 107+/-72 mSv in acute exposure. Standard deviation of the calculated doses is considered to be the dose level below which the effect of radiation becomes undetectable due to the background variation in the effects of all kind of mutagenic factors, i.e., the dose level below which an epidemiological study will not be able to show any significant increase in malignant diseases. The results obtained from epidemiological studies are in fairly good agreement with our results.

Expedient synthesis of potent cannabinoid receptor agonist (-)-CP55,940.

[reaction: see text] A stereocontrolled synthesis of (-)-CP55,940, a potent cannabinoid receptor agonist, has been attained using a novel aldolization/retro-aldolization interconversion strategy, in which a temporarily generated chiral aldol motif plays essential roles.

Organocatalytic entry to chiral bicyclo[3.n.1]alkanones via direct asymmetric intramolecular aldolization.

[reaction: see text] The facile stereoselective syntheses of endo-8-hydroxybicyclo[3.3.1]nonan-2-one and endo-7-hydroxybicyclo[3.2.1]octan-2-one, featuring an alpha-amino acid catalyzed intramolecular aldolization of sigma-symmetric substrates, are described. A high enantioselectivity and a high catalytic efficiency have been exhibited by (4R,2S)-tetrabutylammonium 4-TBDPSoxy-prolinate in the aldolization of 3-(4-oxocyclohexyl)propionaldehyde to give highly enantiomerically enriched (1S,5R,8R)-8-hydroxybicyclo[3.3.1]nonan-2-one.

Effect of smoking on chromosomes compared with that of radiation in the residents of a high-background radiation area in China.

Cytogenetic investigation of stable-type aberrations (translocations) was carried out with our improved methods on 28 elderly individuals in a high-background radiation area (HBRA) in China, and on 24 elderly individuals in a control area (CA). The level of radiation in HBRA is 3 to 5 times higher than in CA. The mean frequencies of translocations per 1,000 cells in HBRA and CA were 12.4 +/- 5.3 and 10.0 +/- 3.8, respectively. No significant difference was found in the frequencies between HBRA and CA (P>0.05, Mann-Whitney U test). When elderly individuals in HBRA and CA were classified into four subgroups of HBRA nonsmokers, HBRA smokers, CA nonsmokers, and CA smokers, a significant difference was found in the frequencies between CA smokers and CA nonsmokers (P<0.05, Mann-Whitney U test). Furthermore a tendency of difference (a near T-value of 0.05 level) was found in a comparison of HBRA smokers vs. CA nonsmokers. The present results indicate that the elevated level of natural radiation in HBRA plays a less significant part than smoking in bringing about the induction rate of stable-type aberrations (translocations) in those areas.

Imperceptible effect of radiation based on stable type chromosome aberrations accumulated in the lymphocytes of residents in the high background radiation area in China.

Cytogenetic investigation of stable type aberrations (translocations) was performed with our improved methods in 6 children and 15 elderly persons in a high background radiation area (HBRA) in China, and in 8 children and 11 elderly persons in a control area. The total numbers of cells analyzed in elderly persons were 68,297 in HBRA and 35,378 in controls and in children were 45,535 in HBRA and 56,198 in controls. On average 5138 cells per subject were analyzed. The variation in the frequencies of translocations per 1000 cells was small in children while it was large in elderly persons. No significant difference was found in the frequencies between HBRA and control (P > 0.05, Mann-Whitney U test). On the other hand, correlation between age and translocation frequencies was significant at the 1% level (rs = 0.658 with 37DF, Spearman rank correlation test). The contribution of an elevated level of natural radiation in HBRA in China to the induction of stable type chromosome aberrations does not have a significant effect compared with the contribution of chemical mutagens and/or metabolic factors. The present study suggests that the probability of the risk of causing malignant and/or congenital diseases by the increased amount of radiation is imperceptible in HBRA where the level of natural radiation is 3 to 5 times higher than that in the control area.

Cancer and non-cancer mortality among Inhabitants in the high background radiation area of Yangjiang, China (1979-1998).

The present study aimed to evaluate the effects of high background radiation (HBR) on mortality. A cohort of 31,604 men and women aged 30-74 y living in the study area in Guangdong Province, China, was followed during the period 1979-1998. The information on deaths and migrations of cohort members was collected by visiting study areas every 3-4 y. Cumulative external radiation dose, lagged by 2 y for leukemia and 10 y for cancer excluding leukemia, was estimated for each individual based on hamlet-specific indoor and outdoor doses, and gender- and age-specific house occupancy factors. The follow-up study accumulated 736,942 person-years at risk and ascertained 6,005 deaths, including 956 cancer deaths and 4,525 non-cancer disease deaths. Mean cumulative radiation doses from natural radiation in the HBR and control area residents were 84.8 mGy and 21.6 mGy, respectively. Mortality due to leukemia (15 deaths) or cancer excluding leukemia (941 deaths) was not related to cumulative radiation dose. The excess relative risk (ERR) Gy of cancer excluding leukemia was estimated to be -1.01 (95% CI: -2.53, 0.95). In site-specific analysis, liver-cancer mortality was inversely related to the cumulative dose (p=0.002). Note, however, that liver cancer is well known for its difficulty in accurate diagnosis. The ERR Gy of cancer excluding leukemia and liver cancer was 0.19 (95% CI: -1.87, 3.04). Non-cancer disease mortality was not related to cumulative radiation dose either. The cumulative HBR dose was not related to the mortality due to cancer or all non-cancer diseases among residents in Yangjiang HBR areas.

Background radiation and cancer incidence in Kerala, India-Karanagappally cohort study.

The coastal belt of Karunagappally, Kerala, India, is known for high background radiation (HBR) from thorium-containing monazite sand. In coastal panchayats, median outdoor radiation levels are more than 4 mGy y-1 and, in certain locations on the coast, it is as high as 70 mGy y-1. Although HBR has been repeatedly shown to increase the frequency of chromosome aberrations in the circulating lymphocytes of exposed persons, its carcinogenic effect is still unproven. A cohort of all 385,103 residents in Karunagappally was established in the 1990's to evaluate health effects of HBR. Based on radiation level measurements, a radiation subcohort consisting of 173,067 residents was chosen. Cancer incidence in this subcohort aged 30-84 y (N = 69,958) was analyzed. Cumulative radiation dose for each individual was estimated based on outdoor and indoor dosimetry of each household, taking into account sex- and age-specific house occupancy factors. Following 69,958 residents for 10.5 years on average, 736,586 person-years of observation were accumulated and 1,379 cancer cases including 30 cases of leukemia were identified by the end of 2005. Poisson regression analysis of cohort data, stratified by sex, attained age, follow-up interval, socio-demographic factors and bidi smoking, showed no excess cancer risk from exposure to terrestrial gamma radiation. The excess relative risk of cancer excluding leukemia was estimated to be -0.13 Gy-1 (95% CI: -0.58, 0.46). In site-specific analysis, no cancer site was significantly related to cumulative radiation dose. Leukemia was not significantly related to HBR, either. Although the statistical power of the study might not be adequate due to the low dose, our cancer incidence study, together with previously reported cancer mortality studies in the HBR area of Yangjiang, China, suggests it is unlikely that estimates of risk at low doses are substantially greater than currently believed.

Total synthesis and absolute stereochemistry of pentenocin B, a novel interleukin-1 beta converting enzyme inhibitor.

Four possible diastereomers of pentenocin B were synthesized in a stereocontrolled manner, and the first total synthesis of a natural enantiomer of (+)-pentenocin B unequivocally established the absolute stereochemistry to be 4S,5R,6R.