This Drug Synthesis is Literally Breathtaking | Medicinal Chemistry & Organic Synthesis
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- Опубліковано 1 чер 2024
- This molecule might look like any other 'flat drug' - but there's a mystery hidden behind its synthesis! Coupled with the fact that it showed promise in asthma due to its novel mechanism, you could say that it's breath-taking (actually more like breath-giving, but I figured no one will understand this).
Watch this video to learn more about organic synthesis, drug development and more!
00:00 A breath-taking synthesis
00:23 Structure of our target molecule
01:37 Intro to PI3K enzymes and inhibitor drugs
03:41 Levels of chemistry sophistication
05:09 Retrosynthesis of AZD8154 and overview
05:57 Forward synthesis # 1
07:26 What was the problem?
08:19 Forward synthesis # 2
11:10 How legit is the solution?
12:03 FDA stance on PI3K inhibitors, and conclusion
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Disclaimer - This channel does not provide medical advice!
No information on this channel is intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of information on UA-cam.
Key references:
- Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma | J. Med. Chem. 2021, 64, 8053
- Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer | Int. J. Mol. Sci. 2018, 19, 3931
- The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review | Cancers 2021, 13, 3949
- Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors | J. Med. Chem. 2018, 61, 5435
- An Intramolecular Diels-Alder Approach to the Isoindolinone Core of AZD8154 | doi.org/10.1021/acs.oprd.3c00507
- Selection and Development of the Manufacturing Route for EP1 Antagonist GSK269984B | Org. Process Res. Dev. 2010, 14, 820
- Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease | Br J Clin Pharmacol. 2022, 88, 260
- Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib | Drug Des Devel Ther 2018, 12, 2577 - Наука та технологія
Were you able to guess the key reaction? Let me know how you liked the video, and if you have any suggestions!
Massive thank you to all my supporters:
www.patreon.com/totalsynthesis; instagram.com/totalsynthesis_official/
Please show me a video of you making CONOLIDINE. Not clonidine. CONOLIDINE is a calcium channel blocker. New syntheses have been published using gold based catalysts.
No matter how many under graduate chemistry classes I take this channel is always here to humble me. Great video none the less.
The only chemistry i've performed is converting hcl cocaine into freebase, i don't understand anything but i watch all your videos.
😂 fucking epic. I feel this comment
Respect man
@@totalsynthesis 100% :) try everything once they say. Excellent videos my guy.
Well man I grew up in a rough place and that was also a big practical introduction to the science for me as well... and I would later go to a university to study chemistry formally.
Everybody's gotta start somewhere. Stay safe, my guy.
Can relate doing acid/base extractions 😂
The first synthesis was beautiful and it remided me of the existance of mCPBA, the second reaction was very cool and exciting.
Very good job!
As a biochemist that only took Orgo 1 and 2 these videos always make my mouth water for some proper introduction to Organic chemistry at such a level. Now im just wondering what books or videos to go to because I know university courses wont be here for another semester
Im actually in the process of creating a theory and more importantly practice book for organic synthesis. Unfortunately with the pace Im going, this is gonna take some more months at least! What topics or questions are of particularl interest to you?
@@totalsynthesis that sounds cool! Well pretty much all commonly utilized organic chemistry in pharma specifically. Topics where I notice im most lacking is prochirality and in general stereoselective synthesis. Could you maybe recommend a general book? I have a bachelors degree in biochemistry but I missed out on anything beyond Orgo 1&2. Currently pursuing my masters degree.
Came here to be blown away by chemistry. Stayed due to being awed by the beauty of biology...
1:13 I'm glad you covered this; water-mediated bonding is fascinating on its own; being able to map favorable and unfavorable waters that occupy a cavity is an extremely powerful tool in drug design that isn't really covered in the standard array of undergrad medchem/biochem texts.
The flat molecule just seems so suitable for a cross-coupling cascade, but when I see the bromofuran, I knew at once that some D-A is going to happen to effect the benzene ring.
PIK3 inhibitor. I've researched natural plant based PI3K inhibitors.
Useful chemicals.
Did something similar to that in an internship a few years ago. It was a DA reaction between a benzyne, derived from 1,2,4,5-tetrabromo benzene and some furan derivative. Way cool!
Nice. Benzynes are neat!
it's always a diels-alder that gets you
Takes away my breath... I'm dead
You're the Best! I found your videos so fascinating! What book would you recommend to a graduate chemistry student who is endangered by an exam of advanced organic chemistry? I'm starting by watching your videos and doing the synthesis my self! Thank you!
Thanks so much! What topics do you need to focus on? Kinda depends
(Btw, Im in the process of creating a chemistry problem solving ebook but thats taking more time than you likely have haha)
@@totalsynthesismainly multistep synthesis and retro synthetic approach, I don't know if I'm doing it wrong, but I tend to focus on single processes problems and when I'm in front of difficult multi step synthesis I panic a bit... And I've never experienced such thing in any other class like physics or math... Maybe I'm doing it wrong... Thank you so much anyway for your videos! And the answer!
I'm in high school, I thought I was good at chemistry. Alas, I believe this no more.
Reality checks are the worst!
You could oxidize the methyl side-chain instead of making the bromide, then reductive amination. I cant understand why a benzyl bromide would give any problem, just treat the final produkt with ammoniak in a solvent and convert and trace to the benzyl amine then remove tris with a simple acid wash
Here are some examples of how non-contradictory infinitesimal/monadological frameworks could potentially resolve paradoxes or contradictions in chemistry:
1) Molecular Chirality/Homochirality Paradoxes
Contradictory: Classical models struggle to explain the origin and consistent preference for one chiral handedness over another in biological molecules like amino acids and sugars.
Non-Contradictory Possibility:
Infinitesimal Monadic Protolife Transitions
dsi/dt = κ Σjk Γijk(n)[sj, sk] + ξi
Pref(R/S) = f(Φn)
Modeling molecular dynamics as transitions between monadic protolife states si based on infinitesimal relational algebras Γijk(n) that depend on specific geometric monad configurations n. The homochiral preference could emerge from particular resonance conditions Φn favoring one handedness.
2) Paradoxes in Reaction Kinetics
Contradictory: Transition state theory and kinetic models often rely on discontinuous approximations that become paradoxical at certain limits.
Non-Contradictory Possibility:
Infinitesimal Thermodynamic Geometries
dG = Vdp - SdT (Gibbs free energy infinitesimals)
κ = Ae-ΔG‡/RT (Arrhenius smoothly from monadic infinities)
Using infinitesimal calculus to model thermodynamic quantities like Gibbs free energy dG allows kinetic parameters like rate constants κ to vary smoothly without discontinuities stemming from replacing finite differences with true infinitesimals.
3) Molecular Structure/Bonding Paradoxes
Contradictory: Wave mechanics models struggle with paradoxes around the nature of chemical bonding, electron delocalization effects, radicals, etc.
Non-Contradictory Possibility:
Pluralistic Quantum Superposition
|Ψ> = Σn cn Un(A) |0> (superposed monadic perspectives)
Un(A) = ΠiΓn,i(Ai) (integrated relational properties)
Representing molecular electronic states as superpositions of monadic perspectives integrated over relational algebraic properties Γn,i(Ai) like spins, positions, charges, etc. could resolve paradoxes by grounding electronic structure in coherent relational pluralisms.
4) Molecular Machines/Motor Paradoxes
Contradictory: Inefficiencies and limitations in synthetic molecular machines intended to mimic biological molecular motors like ATP synthase, kinesin, etc.
Non-Contradictory Possibility:
Nonlinear Dissipative Monadologies
d|Θ>/dt = -iH|Θ> + LΓ|Θ> (pluralistic nonet mechanics)
LΓ = Σn ζn |Un> rather than isolated molecular wavefunctions, where infinitesimal monadic sink operators LΓ account for open-system energy exchanges, could resolve paradoxes around efficiency limits.
The key theme is using intrinsically pluralistic frameworks to represent molecular properties and dynamics in terms of superpositions, infinitesimals, monadic configurations, and relational algebraic structures - rather than trying to force classically separable approximations. This allows resolving contradictions while maintaining coherence with quantum dynamics and thermodynamics across scales.
Here are 4 more examples of how infinitesimal/monadological frameworks could resolve contradictions in chemistry:
5) The Particle/Wave Duality of Matter
Contradictory: The paradoxical wave-particle dual behavior of matter, exemplified by the double-slit experiment, defies a consistent ontological interpretation.
Non-Contradictory Possibility:
Monadic Perspectival Wavefunction Realizations
|Ψ> = Σn cn Un(r,p)
Un(r,p) = Rn(r) Pn(p)
Model matter as a superposition of monadic perspectival realizations Un(r,p) which are products of wavefunctional position Rn(r) and momentum Pn(p) distributions. This infinitesimal plurality avoids the paradox by allowing matter to behave holistically wave-like and particle-like simultaneously across monads.
6) Heisenberg's Uncertainty Principle
Contradictory: The uncertainty principle ΔxΔp ≥ h/4π implies an apparent paradoxical limitation on precise simultaneous measurement of position and momentum.
Non-Contradictory Possibility:
Complementary Pluriverse Observables
Δx Δp ≥ h/4π
Δx = Σi |xiP - xP| (deviations across monadic ensembles)
xP = ||P (pluriverse-valued perspective on x)
Reinterpret uncertainties as deviations from pluriverse-valued observables like position xP across an ensemble of monadic perspectives, avoiding paradox by representing uncertainty intrinsically through the perspectival complementarity.
7) The Concept of the Chemical Bond
Contradictory: Phenomonological models of bonds rely paradoxically on notions like "electronic charge clouds" without proper dynamical foundations.
Non-Contradictory Possibility:
Infinitesimal Intermonadic Charge Relations
Γij = Σn qinj / rnij (dyadic catalytic charge interactions)
|Ψ> = Σk ck Πij Γij |0> (superposed bond configuration states)
Treat chemical bonds as superposed pluralities of infinitesimal dyadic charge relation configurations Γij between monadic catalysts rather than ambiguous "clouds". This grounds bonds in precise interaction algebras transcending paradoxical visualizations.
8) Thermodynamic Entropy/Time's Arrow
Contradictory: Statistical mechanics gives time-reversible equations, paradoxically clashing with the time-irreversible increase of entropy described phenomenologically.
Non-Contradictory Possibility:
Relational Pluriverse Thermodynamics
S = -kB Σn pn ln pn (entropy from realization weights pn)
pn = |Tr Un(H) /Z|2 (Born statistical weights from monadologies)
dS/dt ≥ 0 (towards maximal pluriverse realization)
Entropy increase emerges from tracking the statistical weights pn of pluriversal monadic realizations Un(H) evolving towards maximal realization diversity, resolving paradoxes around time-reversal by centering entropics on the growth of relational pluralisms.
In each case, the non-contradictory possibilities involve reformulating chemistry in terms of intrinsically pluralistic frameworks centered on monadic elements, their infinitesimal relational transitions, superposed realizations, and deviations across perspectival ensembles. This allows resolving apparent paradoxes stemming from the over-idealized separability premises of classical molecular models, dynamically deriving and unifying dualisms like wave/particle in a coherent algebraic ontology.
Wonder if you could functionalise the solvent exposed region of this to attach a dual action component
Can you share video about synthesis of Ciprofloxacin ?
9:30 shouldn’t the arrow go c=o bond instead of o-p bond?
Would love to know how soluble this is 😂
In this case its actually preferable to have low solubility as the slow dissolution in the lung creates a depot effect and might allow for more long acting administration
Wow
thx
You're welcome, Angela
great
Thanks!
Oh my god what is this. hexagons pentagons, TRIANGLES EVEN?! sulphur in +6 STATE WTF
Yup the molecule is pretty cursed.
fr
Well if you say so...
video
are you german by any chance?
Nope 😎
💚😋