3 April 2020 Bulletin

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Ethanol—also called ethyl alcohol, grain alcohol or simply alcohol—is a chemical compound with the formula C2H6O. It is a clear, colourless liquid and readily dissolves in water and other organic compounds. It is naturally produced by fermentation of sugars by petrochemical processes or by yeasts. It is found in overripe fruit and it has also been detected in outer space in interstellar clouds. [1,2]


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Newly discovered ‘magic methyl’ reaction could turbocharge the potency of some drugs

For years, drug discovery chemists have struggled to streamline a process that can boost a drug’s potency up to 2000-fold: “magic methylation.” The reaction sweeps out single hydrogen atoms and replaces them with methyl groups—reshaping the drug molecule to more easily interact with its biological targets. But carrying out this sleight of hand is so difficult that few researchers even try. Now, a team of chemists reports it has created a new catalyst that performs this delicate exchange with ease on a wide variety of druglike molecules, an advance that could lead to novel treatments for everything from cancer to infectious diseases. “This paper is just stunning,” says Tim Cernak, an organic chemist at the University of Michigan, Ann Arbor, who was not involved in the research. The new catalyst manages the reaction in one easy step—a huge improvement on previous multistep methods that were expensive and time-consuming. “This is the wish [of] every drug hunter,” Cernak says. “It really is a dream reaction.” To understand the dream, it helps to know one way chemists build drug molecules, explains M. Christina White, an organic chemist at the University of Illinois, Urbana-Champaign. Most drug molecules contain a skeleton of carbon atoms shaped as a rod or a ring, with multiple hydrogen atoms hanging off each carbon. Chemists act as molecular surgeons, cutting out specific carbon or hydrogen atoms and replacing them with oxygen or nitrogen atoms. If researchers want to add a magic methyl group (which consists of one carbon atom bonded to three hydrogen atoms), they often have to start over, building a new skeleton from scratch. White wanted to find a way to add a methyl group at the end of the drug building process. To do that, she needed to surgically snip one carbon-hydrogen (C-H) bond at a time, without cleaving the other dozen or more C-H bonds in the molecule. Adding further difficulty, C-H bonds are among the strongest in organic molecules, which makes it harder to target just one bond without affecting others, White says. Nature builds and reshapes molecules “in a totally different way,” White says. Chemical changes are made using large, complex enzymes that grasp hydrocarbon scaffolds so that just one C-H bond nuzzles up to the enzyme’s catalytic site—the point at which a reaction takes place. However, each enzyme typically works with only one specific molecule. “If I want to work on a different molecule, I need a new enzyme,” White says. “We want [a reagent that is] just as selective, but general.” In an effort to find just such a catalyst, White and then–graduate student Mark Chen in 2007 devised a snowflake-shaped compound with an iron atom at its center that added oxygen atoms to desired spots in druglike molecules. The catalyst could work as selectively as an enzyme. But it simply didn’t work on a lot of molecular structures or when it was next to a nitrogen atom, which are common in drug molecules. But White’s team kept at it. In 2015, she and her colleagues devised a set of conditions that allowed the iron catalyst and a variant to add oxygen atoms to druglike molecules. And in 2019, they created a similar manganese-based catalyst that performed the oxygen-for-hydrogen swap on druglike molecules containing nitrogen and other common add-ons. But that was just the first step. Now, White’s team reports it has come up with chemical additives that help this latest catalyst complete the “magic methyl” process. After replacing a hydrogen with an oxygen, it steals a methyl group from a reagent known as trimethylaluminum and inserts it in oxygen’s place. White’s team carried out this molecular surgery on 41 different hydrocarbons, including 16 common druglike scaffolds, the researchers report today in Nature. The upshot, White says, is that this reagent will now make it simple and cheap for drug hunters to insert “magic methyl” groups into their molecules. “We hope a lot more drugs with the magic methyl effect will be discovered,” White says. This could help “across the board” in drug discovery, says David Rees, chief scientific officer of Astex Pharmaceuticals. Where adding a methyl group does increase a drug’s potency, doctors may be able to give their patients less of a drug. That could improve safety and reduce side effects. Among the drugmakers he knows, Rees says, “Everyone will jump on this.”



Requirement to Report Accidental Releases to Chemical Safety Board Takes Effect

Under a new rule effective on Monday, March 23, 2020, owners and operators of stationary sources are required to report qualifying accidental releases to the ambient air of hazardous substances to the federal Chemical Safety and Hazard Investigation Board (CSB). While many companies are currently consumed with handling operations and logistics related to the coronavirus pandemic, compliance will still be expected going forward. Importantly, however, the CSB’s preamble to the new rule expresses a one-year grace period from the effective date of the rule, during which it will refrain from referring reporting violations for enforcement absent a knowing failure to report. The extent of this reporting obligation will vary depending on whether reporting to the National Response Center (NRC) is also required and has been accomplished. Detailed reporting to the CSB may be required for certain accidental releases. However, if a release report has already been submitted to the NRC pursuant to the federal Comprehensive Response, Compensation, and Liability Act (CERCLA), a facility need only submit the NRC identification number to the CSB. Who is the CSB? The CSB is an independent federal agency established by the federal Clean Air Act Amendments of 1990 (CAA) and tasked with investigating industrial chemical accidents. The CSB reports its findings on the cause of chemical releases and makes recommendations to facilities and federal agencies, like the Environmental Protection Agency (EPA) and Occupational Safety and Health Administration (OSHA), with an aim to reduce the likelihood and consequences of accidental releases in the future. The CSB published its final rule on Accidental Release Reporting, codified at 40 C.F.R. Part 1604, in February 2020, and the rule took effect on March 23, 2020. What type of release must be reported to the CSB? Any accidental release that results in a fatality, serious injury (i.e., results in hospitalization), or property damage at or outside the stationary source that is estimated to be equal to or greater than $1,000,000 must be reported. Key definitions follow: ● An “accidental release” is “an unanticipated emission of a regulated substance or other extremely hazardous substance into the ambient air from a stationary source.” ● “Regulated substances” and “extremely hazardous substances” include those substances listed under CAA Section 112(r)(3), 42 U.S.C. § 7412(r)(3), and its accompanying regulation, 40 C.F.R. § 68.130, as well as any other substance that may cause death, serious injury, or substantial property damage. ● “Ambient air” includes “any portion of the atmosphere inside or outside a stationary source.” ● “Stationary sources” include “any buildings, structures, equipment, installations, or substance-emitting stationary activities which belong to the same industrial group, which are located on one or more contiguous properties, which are under the control of the same person (or persons under common control), and from which an accidental release may occur.” When is reporting to the CSB required? In general, an owner or operator is required to submit a report to the CSB within eight hours of the accidental release. However, if a facility has a release of a reportable quantity of a hazardous substance that has already been reported to the NRC as required, the facility need only report the NRC identification number to the CSB within 30 minutes of submitting a report to the NRC. What information must be included in a report? Except where already reported to the NRC, the following information must be reported to the CSB: • the name of, and contact information for, the owner or operator; • the name of, and contact information for, the person making the report; • the location information and EPA facility identification number; • the approximate time of the accidental release; • a brief description of the accidental release; • an indication whether the accidental release entailed a (1) fire; (2) explosion; (3) death; (4) serious injury; or (5) property damage; • the name of the hazardous substance(s) released, as well as the Chemical Abstract Service (CAS) number(s) or other appropriate identifiers; • the amount of the release, if known; • the number of fatalities, if known; • the number of serious injuries, if known; • estimated property damage at or outside the stationary source; an • whether the accidental release has resulted in an evacuation order impacting members of the general public and others, and, if known, information about the scope of the evacuation order How must CSB reporting be submitted? Reports are to be made by email to report@csb.gov or by telephone at (202) 261-7600. Can information reported to the CSB be revised? Yes. An owner or operator is permitted to revise or update a report made to the CSB via email to report@csb.gov or by letter to CSB 1750 Pennsylvania Ave. NW, Suite 910, Washington, DC 20006, within 30 days following the submission of the initial report to the NRC or CSB. An update may also be submitted up to 90 days following the submission of an initial report, but the email or letter must explain why the revised report could not have been provided within the first 30 days. Is there a grace period for enforcement? Yes. As mentioned above, the preamble to the final rule that there will be a one-year grace period from the effective date of the rule, during which time it will refrain from referring reporting violations for enforcement, unless there is a knowing failure to report.


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