Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer)

Studies of the reactions between indole- 2,3-diones (isatins) and 2-aminobenzylamine

Abstract-Reflux of equimolecular amounts 2-aminobenzylamine and isatins in acetic acid produced indolo[3,2-c]quinolin-6-ones in good yields. A proposed mechanism involving initial formation of a spiro compound is given. This isolable intermediate subsequently rearranges via a sequential isocyanate ring opening and a cyclisation process to a urea derivative which finally cyclized to the indolo[3,2-c]quinolin-6-ones. The urea derivative could be prepared separately and cyclized selectively to indolo[3,2-c]quinolin-6-one. Reaction of N-acetylisatin with 2-aminobenzylamine at room temperature yielded the 1,4-benzodiazepinone 3-(2-acetamidophenyl)-1,5-dihydro-1,4-benzodiazepin-2-one whereas its isomer 2(2-acetamidophenyl)-4,5-dihydro-1,4-benzodiazepin-3-one was obtained from 2-(2-acetylaminophenyl)-N-(2-aminobenzyl)-2-oxoacetamide in acetic acid at room temperature.The previously unknown linear isomer of indolo[3,2-c]quinolin-6-one, i.e. indolo [2,3-b]quinolin-11-one, has been prepared by thermal (2608C) cyclization of methyl 2-phenylamino indole-3-carboxylate, which in turn was prepared in two steps from methyl indole-3-carboxylate.

Per-Olof Åstrand : Nekrolog

Nekrolog över Per-Olof Åstrand Professor emeritus Per-Olof Åstrand har avlidit i en ålder av 92 år. Hans närmaste anhöriga är makan Irma och barnen Elin och Per med familjer. Per-Olof Åstrand föddes i Bredaryd i Småland den 21 oktober 1922, och avled den 2 januari 2015 i Näsby Park norr om Stockholm. Efter värnplikt och beredskapstjänstgöring i pansartrupperna under andra världskriget kom han 1944 till Kungl. Gymnastiska Centralinstitutet (GCI/GIH) för studier till gymnastiklärare. Vid sluttentamen i fysiologi var hans svar så avancerade att den ansvarige läraren bad professorn, Erik Hohwü Christensen, att rätta dem. Kort därefter fick GCI:s fysiologiska institution en ny amanuens. Efter gymnastikdirektörsexamen 1946 följde läkarstudier, och parallellt med dessa inleddes avhandlingsarbetet  ”Experimental studies of physical working capacity in relation to sex and age”, som försvarades 1952. Genom detta utvecklades en metodik för att mäta maximal syreupptagning. Det blev en avgörande variabel att relatera till i hans senare forskning om den cirkulatoriska och respiratoriska anpassningen till fysiskt arbete och träning. Det submaximala konditionstest som P.-O., och hans blivande hustru Irma Ryhming, publicerade år 1954 bidrog till att göra GCI känt över världen. Det finns fog att benämna honom som ”den vetenskapligt baserade konditionsträningens fader”. 1970 blev han professor i kroppsövningarnas fysiologi vid GIH. P.-O. visade tidigt ett stort intresse för undervisning, och många mötte honom i populärvetenskapliga skrifter såsom ”Kondition och hälsa” och ”Bättre kondition”, men det var genom den omfattande läroboken ”Textbook of Work Physiology: Physiological Bases for Exercise”, skriven tillsammans med Kaare Rodahl, som han blev det riktigt stora namnet inom internationell arbetsfysiologi. Där framträdde holisten Åstrand med en bredd och ett djup som ingen förr hade fångat och skrivit fram. Denna bok, P.-O:s pedagogiska förmåga och engagemang har haft avgörande betydelse för många studenter och kolleger. Hans gärningar gjorde honom till ledamot i många lärda sällskap och hedersdoktor vid ett antal universitet ute i världen. Därtill var han en hedersman, med en personlighet präglad av en stor omtanke, slagkraftig humor och generös spiritualitet, ofta med inslag av en särpräglad musikalisk förmåga. För oss som studenter och lärare vid GIH kom samvaron med P.-O. ofta att formas till högtidsstunder. En legendar har nu lämnat oss i djupaste sorg, men också i tacksamhet över allt han bidrog med i våra liv. Jan Henriksson Hans Rosdahl Peter Schantz Harriet Wallber

The influence of hemicelluloses during the precipitation of lignin in kraft black liquor

Removing lignin from black liquor is one way of recovering valuable organic substances for alternative use as well as reducing the energy surplus in a modern, energy-optimised kraft pulp mill. By using the recently developed "LignoBoost" process it is possible to upgrade black liquor streams of different origin to form valuable chemicals. In this investigation a combination of membrane filtration and the LignoBoost concept was used. The primary objective of the work was to investigate whether or not the filtration properties of the black liquor were affected by its hemicellulose content. The hemicellulose content in the black liquors was lowered prior to precipitation using three different pre-treatment techniques, and the filtration properties were compared to the reference black liquors of evaporated softwood and hardwood black liquor. The pre-treatment methods used were heat-treatment, ultrafiltration and a combination of ultrafiltration and nanofiltration. It was shown that the filtration resistance was lowered considerably when the hemicellulose content in the black liquor was reduced prior to precipitation. The experiments also showed that it was possible to produce a hardwood lignin product of high purity i.e. low sodium (0.2 w-% of TIDS) and hemicellulose content (0.7 w-% of TDS

Synthesis of P1 '-Functionalized Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol

Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the para position of the benzyl group in the P1' side with (hetero)aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1-P3 macro-cyclization, 14- and 15-membered macrocyclic Pis were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound 101, with a 2-thiazoly1 group in the P1' position, was the most potent PI of this new series (K-1 2.2 nM, EC50 0.2 mu M). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed

Design and Synthesis of P1-P3 Macrocyclic Tertiary-Alcohol-Comprising HIV-1 Protease Inhibitors

To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with K-i and EC50 values down to 3.1 nM and 0.37 mu M, respectively

Synthesis of P1′-Functionalized Macrocyclic Transition-State Mimicking HIV‑1 Protease Inhibitors Encompassing a Tertiary Alcohol

Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the <i>para</i> position of the benzyl group in the P1′ side with (hetero)­aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1–P3 macrocyclization, 14- and 15-membered macrocyclic PIs were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound <b>10f</b>, with a 2-thiazolyl group in the P1′ position, was the most potent PI of this new series (<i>K</i>_i 2.2 nM, EC₅₀ 0.2 μM). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed