ABSTRACT
The approach to reproductive health and safety in academic laboratories requires increased focus and a shift in paradigm. Our analysis of the current guidance from more than 100 academic institutions' Chemical Hygiene Plans (CHPs) indicates that the burden to implement laboratory reproductive health and safety practices is often placed on those already pregnant or planning conception. We also found inconsistencies in the classification of potential reproductive toxins by resources generally considered to be authoritative, adding further confusion. In the interest of human health and safe laboratory practice, we suggest straightforward changes that institutions and individual laboratories can make to address these present deficiencies: Provide consistent and clear information to laboratory researchers about reproductive health and normalize the discussion of reproductive health among all researchers. Doing so will promote safer and more inclusive laboratory environments.
Subject(s)
Hazardous Substances/adverse effects , Laboratories , Occupational Health , Organic Chemicals/adverse effects , Research Personnel , Safety Management , Female , Hazardous Substances/chemistry , Humans , Organic Chemicals/chemistry , Pregnancy , United States , United States Occupational Safety and Health AdministrationABSTRACT
Molnupiravir (MK-4482, EIDD-2801) is a promising orally bioavailable drug candidate for the treatment of COVID-19. Herein, we describe a supply-centered and chromatography-free synthesis of molnupiravir from cytidine, consisting of two steps: a selective enzymatic acylation followed by transamination to yield the final drug product. Both steps have been successfully performed on a decagram scale: the first step at 200 g and the second step at 80 g. Overall, molnupiravir has been obtained in a 41% overall isolated yield compared to a maximum 17% isolated yield in the patented route. This route provides many advantages to the initial route described in the patent literature and would decrease the cost of this pharmaceutical should it prove safe and efficacious in ongoing clinical trials.
ABSTRACT
A macrocyclic motif fosters productive protein-small molecule interactions. There are numerous examples of both natural product and designed, synthetic macrocycles that modulate the immune system, slow microbial infection, or kill eukaryotic cells. Reported here are the synthesis, physicochemical characterization, and antiproliferative activity of a group of [13]-macrodilactones decorated with a pendant biaryl moiety. Biaryl analogs were prepared by Suzuki reactions conducted on a common intermediate that contained a bromophenyl unit alpha to one of the carbonyls of the [13]-macrodilactone. Principal component analysis placed the new compounds in physicochemical context relative to a variety of pharmaceuticals and natural products. Modest inhibition of proliferation was observed in ASZ cells, a murine basal cell carcinoma line. This work underscores the value of an approach toward the identification of bioactive compounds that places the evaluation of physicochemical parameters early in the search process.
Subject(s)
Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Lactones/pharmacology , Macrocyclic Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Lactones/chemical synthesis , Lactones/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating groups and proceed in overall yield of 75%, a significant advancement over the reported yield of 17%. The step count is reduced from five transformations to two, and expensive uridine is replaced with the more available cytidine.
Subject(s)
Cytidine/analogs & derivatives , Cytidine/chemistry , Hydroxylamines/chemistry , Acylation , KineticsABSTRACT
Skipped polyenes featuring high ( E)-selectivity and varying methyl substitution patterns are synthesized using a nickel-catalyzed cross-coupling reaction between allyl trifluoroacetates and vinyl bromides. The utility of this cross-electrophile coupling is showcased in part by the synthesis of the RST fragment of the marine ladder polyether, maitotoxin. Construction of this fragment is particularly challenging due to the alternating methyl substitution pattern.