Přírodní látky a jejich role ve vývoji léčiv

Příprava předmětu byla podpořena projektem OPPA č. CZ.2.17/3.1.00/33253

Overview 1/2 Opium/morphine alkaloids

a) Epoxymorphinanes (Morphine, codeine, thebaine, pholcodine, hydrocodone group, oxycodone group, nalbuphine, buprenorphine)

b) Morphinanes (Levorphanol, dextromethorphan, butorphanol) c) Benzomorhanes (Methazocine, pentazocine, phenazocine) d) Tapentadol (history, synthesis) Antimalarics

a) Quinine b) Synthetic APIs (Chloroquine, mefloquine, trimethoprim, pyrimethamine,

artemisinin group) Antibacterials

a) Quinolone group (discovery, nalidixic acid, oxolinic acid) b) 6-Fluoroquinolone group (Norfloxacin, ciprofloxacin, ofloxacin, …) c) Penicillins (discovery, Sheehan´s synthesis, β-lactam antibiotics) d) Cephalosporins and cephamycins e) Penems

Overview 2/2

Natural products in cancer treatment a) Bis-indole alkaloids b) Vincaleucoblastine and vincristine (history, partial synthesis) c) Further bisindoles (Vindesine, vinorelbine, vinflunine, future) d) Taxol group (paclitaxel, history, partial synthesis, taxotere,

advanced DFs) Further drugs based on NP

a) Orlistat (from lipstatine, TS by Hanson) b) Ecteinascidine 743 (story, TS by Corey, phthalascidin) Further topics

a) Classification of NP based drugs b) Potential of NP/why to synthesize them c) Inib group d) Graphical overviews of new drugs/cancerostatics e) Prospect

History of natural products

traditional medicine opium air-dried milky exudate from incised, unripe capsules of poppy Papaver

somniferum well known in ancient world, Greece Hippocrates – use of poppy juice as a hypnotic, narcotic, cathartic and

styptic Pliny the Elder – use of the seeds as a hypnotic, use of the latex for headaches, arthritis and curing wounds Dioscorides (77 AD) – two forms: latex of the capsules, whole plant

extract cultivation of opium spread from Asia Minor to Persia to India and

China smoking of opium in Far East and China extensive already at the end of

18th century

Morphine alkaloids (morphinanedienones) both skeleton enantiomers genus Papaver genera Sinomenium, Stephania opium (Papaver): morphine, codeine, thebaine, oripavine, … poppy straw (capsules + stems) alternative/industrial source (1951: 17% of 70 t; 1971: 37% of 170 t)

NH

HO

HO

O

H NH

MeO

HO

O

H N

MeO

MeO

O

H(-)-morphine Opium: 4-21%

Isolation: 1803-4 Structure: 1925 (Robinson) T.S.: 1952 (Gates, 20 steps)

Pain relief (analgesia)

(-)-codeine Opium: 0.7-2.5%

Important analgetic and antitussive drug

(-)-thebaine Opium: low content Papaver bracteatum

Toxic, important starting material

Pholcodine antitussive, with analgesia suppressed

NH

O

HO

O

H

NO

NH

HO

HO

O

HN

H

O

HO

O

H

NOCl

NO NaOH

Thebaine in synthesis thebaine serves as starting material for diverse array of compounds

Hydrocodone Analgesic (narcotic)

Antitussive

Oxycodone analgesic

Butorphanol Analgesic (narcotic)

antitussive

Naloxone Narcotic antagonist

Naltrexone Narcotic antagonist

In treatment of alcoholism

N

MeO

MeO

O

H

NOH

MeO

O

O

H

NH

MeO

HO

O

HN

H

MeO

O

O

H

H+ [H]

H2O2, AcOH

NOH

MeO

O

O

HN

OH

HO

NOH

HO

O

O

HN

OH

HO

O

O

H

NH

MeO

O

O

H

Oripavine Useful

intermediate

N

HO

MeO

O

H

6-Oxo group Analgesic Merck, patent from 1925

Hydrocodone antitussive, narcotic analgesic

Hydromorphone analgesic

Oxymorphone analgesic

NH

MeO

O

O

H

NH

HO

HO

O

H

PhN+Me3 Cl-,KOH, MeOH

NH

MeO

HO

O

HN

OH

MeO

O

O

H

Pd or Pt cat., heat

NH

HO

O

O

H

Pd or Pt cat., heat

1) K2Cr2O7, AcOH2) H2, Pd cat.

HBr aq, 120 oC

NOH

HO

O

O

H

Oxycodone analgesic

Naloxone and naltrexone Narcotic antagonists Developed in 60´s

Naltrexone Naloxone

NOH

HO

O

O

HN

OAcCN

AcO

O

O

HNH

OH

HO

O

O

H

NOH

HO

O

O

H

CH2=CHCH2Br,NaHCO3

1) Ac2O2) BrCN HCl aq, ∆

BrDMF, 70 oC, 1 week

NOH

HO

O

O

HN

OH

O

OO

O

O

O

H

A

Available from A

1) LiAlH42) NH4Cl3) HCl aq

Nalbuphine Morphine antagonist, analgesic Developed in 60´s

NHOH

HO

O

O

H

A

COClbase, DCM

NOH

O

O

O

H

NHOH

HO

HO

O

H

NaBH4, EtOH LiAlH4

NOH

HO

HO

O

H

Br

OO

Nalfurafine kappa-opioid agonist, analgesic Developed in 90´s Toray (Originator), Fujisawa (Marketer), Daiichi Pharm (Licensee)

Schnider O., et al.: Chem. Pharm. Bull. 1998, 46, 366.

BnNHMe, NaBH3CN

H2, Pd/C

NOH

HO

O

O

H

Naltrexone

NOH

HO

N

O

H

NOH

HO

HN

O

HN

OH

HO

N

O

HO

O

NaOH

MeNH2, H2, PtO2

COCl

O

Buprenorphine from thebaine Analgesic; treatment of opioid dependence [4+2] cycloaddition of thebaine with MVK as the crucial skeleton building

step

Overall yield 9 % (6 steps)

N

MeO

MeO

O

O

HH

N

HO

MeO

O

HO

HH

BrCN, CH2Cl2

N

MeO

MeO

O

HHN

MeO

MeO

O

HO

HH

N

MeO

MeO

O

HO

HH

1) H2, Pd/C2) t-BuMgBr

NH

HO

MeO

O

HO

HHCN

KOH, LiOH (kat), 180-190 °C

C3H5CH2Br,Na2CO3, MEK

70%

O

+

75 + 50%

80%

60%70%

H

HHH

Levorfanol Roche: analgesic Optical resolution at the final stage (±)-A as an intermediate in synthesis of

dextrometorfan NH

HO

OCN

COOH

CN

COOH

CN

NH2NH

OMe

O

COCl

MeON

OMe

NC-CH2-COOH,AcONH4

H2, Ra-Ni

basePOCl3

Bischler-Napieralskii

Schnider O., et al.: Helv. Chim. Acta 1950, 33, 1437; Ibid. 1951, 34, 2211.

Levorfanol Roche: analgesic Optical resolution at the final stage (±)-A as an intermediate in synthesis of

dextrometorfan NH

HO

N

OMe

NH

HO

NH

HO

H3PO4

(+)-tartaric acid

Cyclization

Resolution

(±)-A(-)-A

NH

OMe

H2, Ra-Ni N

OMe

CH2=O, H2, Ra-Ni

Schnider O., et al.: Helv. Chim. Acta 1950, 33, 1437; Ibid. 1951, 34, 2211.

Dextromethorphan Roche: antitussive, not addictive From (±)-A, the intermediate in synthesis of

levorphanol Optical resolution at the final stage

Schnider O., et al.: Helv. Chim. Acta 1951, 34, 2211.

NH

MeO

NH

MeO

NH

HO

(±)-A

PhMe3N+ Cl-,NaOMe, MeOH

NH

MeO

(±)-B

(-)-tartaric acid

Resolution

(+)-B

Butorphanol 1/2 – from thebaine VÚFB synthesis from thebaine through dihydrohydroxycodeinone

N

MeO

MeO

O

HN

OH

MeO

O

O

H

NOH

MeO

1) H2O2, AcOH2) H2, Pd/C

1) Zn, HCl aq2) PhBr, Zn/Cu

NOH

MeO

PhO

NOH

CN

MeO

1) Li/NH3 liq2) BrCN

1) Hydrolysis2) c-C4H7COCl

NOH

HO

O1) LiAlH42) BBr3

Oxycodone

Butorphanol 2/2 – total synthesis Bristol-Myers: anisol and succinic acid anhydride as starting materials; several variants patented

O

MeO

NH

MeO

O

MeO

HO

MeO

H2N

BrBr

1) MeCN, n-BuLi2) LiAlH4Base

MeO

H2N

HCl, Et2O

NH2

MeO

NH.HBr

MeO

Br

Br2, CHCl3NaHCO3, DMF

N.HBr

MeO

NaHCO3, DMF, 130 oC

1) TFAA2) m-CPBA

N

MeO

COCF3OH

NH

MeO1) NaBH4, EtOH, rfl2) LiAlH43) Resolution

OHN

OH

HO

Benzomorphanes Methazocine (A) analgesic intermediate in synthesis of pentazocine

and phenazocine the last of the three disclosed

N

N

HO

HBr

Cyclization

N

OMe

N

OMe

NMeII- MgCl

MeO

H2, Pd or NaBH4

HO

NH

A

NH

HO

N

HO

A

Archer S., et al.: J. Med. Chem. 1964, 7, 123.

Benzomorphanes Pentazocine (B), Phenazocine (C) B: Sanofi Winthrop C: Smith Kline & French analgesic

Archer S., et al.: J. Med. Chem. 1964, 7, 123; May E. L, et al.: J. Org. Chem. 1957, 22, 1366, 1369;.Ibid. 1959, 24, 1435; Ibid. 1960, 25, 984.

N

HO

B

1) Ac2O2) BrCN3) H3O+, heat

HO

NH

HO

NHH

alternatively with ClCOOR

HO

NH

Me2C=CHCH2Br,K2CO3

B

HO

NH

O

PhCH2COCl

HO

NH

C

LiAlH4

N

HO

C

Benzomorphanes Phenazocine (C) Smith Kline & French: analgesic

May E. L, et al.: J. Org. Chem. 1957, 22, 1366, 1369;.Ibid. 1959, 24, 1435; Ibid. 1960, 25, 984.

N

HO

C

N

N

HO

HBr

Cyclization

N

OMe

N

OMe

NPhCH2CH2BrBr- MgCl

MeO

H2, Pd

HO

NH

C

New analgesic agents Tapentadol CNS-Pain/moderate-to-severe acute pain in adults Mode of action: µ-opioid receptor agonist and

norepinephrine reuptake inhibition Johnson &Johnson, Gruenenthal co-developing in EU 2 chiral centers, single (R,R)-enantiomer

NHO

NHO

NH

HO

HO

ON

MeO

HO

Morphine Tramadol

New analgesic agents Tapentadol CNS-Pain/moderate-to-severe acute pain in adults Known syntheses N

HO

O

N

MeOO

N

MeO NCl

MeO N

MeO NOH1) RMgBr, THF

2) Opt. resolution SOCl2

NaBH4, ZnCl2,Et2O

MeO N

and (asym) hydrogenation

MeON

O

TFAA, 2-MeTHFHCl aq

H2, Pd/C

O CF3

New analgesic agents Tapentadol CNS-Pain/moderate-to-severe acute pain in adults Tapentadol is the first new molecular entity entering

medical practice in the oral opioid category in over 25 years New strategy based on Claisen rearrangement of ester

enolates

NHO

NHO COOHRO CHORO

ROO

ROO

O

or

ROOH

(EtCO)2O CH2=CHCH2Br+ +

New analgesic agents Tapentadol CNS-Pain/moderate-to-severe acute pain in adults Crucial Claisen rearrangement of ester enolate Metallation by LiHMDS/Et3N mixture afforded superior

results, see reference below

NHO

Run PG LHMDS [equiv]

Et3N [equiv]

Temp. [°C]

Erythro/threo Yield [%]

1 Me 1.5 15 -70 80:20 15 2 Bn 2.9 0 -60 11:1 29 3 Me 3 30 - 35 >95:5 47 4 Me 2,5 25 - 65 >95:5 78 5 Me 3 3 - 65 >97:3 87 6 Bn 6 8 -65 50:1 88 7 Bn 2,8 2,9 - 75 97:3 98

COOHPGOPGOO

O LiHMDS, Et3N,PhMe COOHPGO

+

Godenschwager P. F., Collum D. B.: J. Am. Chem. Soc. 2008, 130, 8726 .

New analgesic agents Tapentadol CNS-Pain/moderate-to-severe acute pain in adults Late stages of the synthesis A variant starting with hydrogenolysis of the Bn group

equally efficient

NHO

COOHBnO CONMe2BnO1) SOCl22) Me2NH

BnO NNHO H2, 5% Pd/C

Synhydrid, PhMe, 100 °Cor LiAlH4, THF

Malaria and the role of quinine

1633 first report on use of cinchona bark against malaria (Plasmodium) cinchona – dried bark of Cinchona officinalis, C. succirubrum, C. calisaya, C.

ledgeriana one of the key factors in colonisation of Africa and Asia by Great Britain and

Holland cinchona was the only antimalaric up to WW II

(-)-quinine Isolation: 1820 (Pelletier, Caventou)

Structure: 1908 (Rabe) Synthesis: 1944 (Woodward, Doering)

antimalarial; muscle relaxant (skeletal);

flavor in carbonated beverages

N

NHO

HX

X = H CinchonineX = OMe Quinidine

N

NHO

HX

X = H CinchonidineX = OMe Quinine

18

5

78

13

14

2 3

15

162021 N

HN

H

OHC

23

578

13

1415

16

20

18

21

Biosynthetic precursor

Antimalarics

Overview Development of several synthetic antimalarics Development of resistance of Plasmodium sp. to synthetic drugs Quinine still in use (rare resistance) WHO recommendation to use combination therapy;

N

HN

N

NEt2NH

CF3Cl

CF3

HOH

Chloroquine

Mefloquine

N

NH2N

ClPyrimethamine

O

OH

OO

H

HO

Artemisinin

O

OH

OO

H

HO

Artesunate

O

COOH

Antimalarics

Several groups Quinolines with 4-substituent (including basic function) –chloroquine,

mefloquine (interaction with DNA of protozoon); Pyrimidines – pyrimethamine Sesquiterpenoid lactones – artemisinin (from shrub Artemisia annua,

used in chinese medicine for ca. 15 centuries, also antitumor properties) and analogs (against resistent streams).

N

HN

N

NEt2NH

CF3Cl

CF3

HOH

Chloroquine

Mefloquine

N

NH2N

ClPyrimethamine

O

OH

OO

H

HO

Artemisinin

O

OH

OO

H

HO

Artesunate

O

COOH

Chloroquine The first antimalaric Chloroquine discovered 1934, later abandoned and rediscovered 1945 Important antimalaric drug till today

N

Cl

Cl

Cl NH2

EtOOC COOEt

OEtCl

EtOOC COOEt

N Cl

COOEt

NH

heat

O

1) Hydrolysis (OH-)2) Decarboxylation (Cu)3) POCl3

N

HNNEt2

ClHN

NEt2NaH

NCl

COOHO

NN

COOHO

B

A

Antimalarics - mefloquine Basic information Sold as racemate (adverse neurological effects); (R)-enantiomer more active (S)-enantiomer side effects

many syntheses, development continues EP 2233481 A1 diastereoselective hydrogenation of dehydromefloquine in the presence of bromide ions in acid medium

N

NH

CF3CF3

HOH

NH2

CF3

F3CCOCH2COOEtheat N CF3

CF3

OH

N CF3CF3

Br

BuLi, then AN CHO

A

N

N

CF3CF3

HO

H2, PtO2

POBr3

Antimalarics - trimethoprim Basic information inhibits synthesis of folic acid used also in combi-medicine for the treatment of infections

OMe

OHOMe

OMe

OHOMe

CH2=O, Me2NHMe2N

OMe

OOMe

N

N

OH

HO

N

N

NH2

H2N

1) POCl32) NH3 aq

OMe

OHOMe

N

N

NH2

H2N

MeBr

heat

OMe

OMeOMe

N

N

NH2

H2N

Antimalarics - pyrimethamine Basic information inhibits synthesis of folic acid

Cl

CN

Cl

CNMeCH2COOEt,NaOEt

O

Cl

CN

OMe

CH2N2

Cl

N

N

NH2

NH2

H2N NH2

NHNaOEt

Antimalarics – artemisinin family

Recent developments Artemisinin from Artemisia annua (druh pelyňku); Artemether and artesunate also from A. annua in minor amounts, made

semisynthetically; Development of resistance of Plasmodium sp. to drugs WHO recommendation to use combination therapy; ACT = artemisinin combi-therapy, especially with artesunate

Recent patent application on artesunate synthesis: WO 2008/087667.

O

OH

OO

H

HO

O

OH

OO

H

HO

O

COOH

1) NaBH4, MeCH(OH)CH2OH,i-PrOH, hexane

2) Succinic anhydride,imidazole, DCM

Antibacterials and chloroquine

Story begun with testing compound A, impurity in chloroquine prepared by the route shown below Nalidixic acid (B) launched 1963 (1st generation of quinolone antibiotics)

N

Cl

Cl

Cl NH2

EtOOC COOEt

OEtCl

EtOOC COOEt

N Cl

COOEt

NH

heat

O

1) Hydrolysis (OH-)2) Decarboxylation (Cu)3) POCl3

N

HNNEt2

ClHN

NEt2NaH

NCl

COOHO

NN

COOHO

B

A

Nalidixic acid Basic information 1st generation

NH2

EtOOC COOEt

OEt

EtOOC COOEt

N

COOEt

NH

heat

O

1) EtI, base2) Hydrolysis (OH-)

N

COOHO

Oxolinic acid Basic information 1st generation

EtOOC COOEt

OEtCOOEt

NH

heat

O

1) EtI, base2) Hydrolysis (OH-)

N

COOHO

O

O

O

O NH2

O

O

O

O

1) HNO3, H2SO42) H2, Ra-Ni

6-Fluoroquinolones Key features Fluorine at C-6 enhances activity, lowers toxicity as well as broadens the

spectrum of action; Dialkylamino group at C-7 also benefitial, especially if incorporated in a

saturated heterocycle; Ethyl group at N-1 (or isostere like cyclopropyl, vinyl, ...); 3rd generation antibiotics:

NN

COOHO

HN

F

NN

COOHO

N

F

O

Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin [(-)-S]

NN

COOHO

HN

F

Fluoroquinolones

R = Et Norfloxacin R = c-C3H5 Ciprofloxacin

F

Cl Cl

F

Cl Cl

1) AcCl, AlCl32) NaBrO COOH F

Cl Cl

OCOOEt

O)2MgEtO

COOEt

1) SOCl2

2)

3) TsOH, H2OAc2O, HC(OEt)3

F

Cl Cl

OCOOEt

OEt

F

Cl Cl

OCOOEt

NHR

RNH2F

Cl N

OCOOEt

NaH

1) Hydrolysis (H+)2)

HNNH

R

F

N N

OCOOH

RHN

Ofloxacin Widely used (also ciprofloxacin)

F

F NO2F

F

F NO2F

1) KOH2) MeCOCH2Cl,

KI, Na2CO3

F

F NHO

H2, Ra-Ni

EtOOC COOEt

OEt

F

F NO

EtOOC COOEt1) PPA2) Hydrolysis (H+)

3)

NNHNN

COOHO

N

F

O

Fluoroquinolones – newer ending story Many newer structural variants developed; The most important is trovafloxacin (highly active against resistent

bacterial streams)

N

COOHO

F

N

NH H

H

OMeNN

COOHO

F

N

H2N

H

H

F

F

Moxifloxacin

Trovafloxacin

Penicillin story mold Penicillium notatum penicillin capable of destroying pathogenic bacteria Fleming, Florey, Chain – Nobel prize 1945 massive program during WWII structure elucidation chemical synthesis development large-scale production by fermentation feasible many lives saved during WWII and after prominent place in medicinal products structural lability due to the strained ß–lactam moiety, which is

responsible for antibacterial properties biosynthesis from valine and cysteine (also dipeptidic antibiotics)

N

S

OCOOH

RHN H

Penicillin V synthesis 1/3 lability of the strained ß–lactam = synthesis „impossible problem“ Sheehan J. C., MIT, 1957

N

S

OCOOH

HN H

OO

H2N

HS

COOHCOOt -Bu

CHON

O

O

+

D-Penicillamine(hydrochloride)racemic

new synthetic reactions have been developed en route to the target new methods for ß–lactam synthesis method for ß–lactam formation through lactamization (DCCI)

(-)-penicillamine Antirheumatic Wilson´s

disease treatment

Penicillin V synthesis 2/3

epimerization of B by hot pyridine, A crystallizes upon cooling cleavage of t-butyl ester by anhydrous HCl (option: hydrogenolysis of benzyl ester)

H2N

HS

COOHCOOt-Bu

CHON

O

O

+

COOt-Bu

N

O

O

NH

S H

A ß-PhthNB α-PhthN

NaOAc, EtOH aq

py, heat

[on A]1) N2H4, 13 °C2) dil HCl aq (acidification)

COOt-Bu

HCl.H2N NH

SCOOHH

82%COOt -Bu

HN N

H

SCOOHH

PhOCH2COCl,Et3N

O

1) HCl, DCM, 0 °C2) py (1 eq),

acetone aq

PhO

COOH

HN N

H

SCOOHH

O

PhO

70%100%

Penicillin V synthesis 3/3

lactamization by DCCI method (usually high yields) competitive azlactonization due to Lewis-basic acetamide oxygen

COOH

HN N

H

S COOHH

O

PhO HN N

H

S COOKH

O

PhO

OO

C6H11N NHC6H11

H

1) KOH (1 eq),2) DCCI (4 eq),

dioxane aqN

S

OCOOK

HN H

OO

10-12%

HN N

H

S COOKH

O

PhO

OO

C6H11N NHC6H11

H

N NH

S COOHH

O

PhO

O

+

Improvement of lactamization

suppression of azlactone formation 6-aminopenicillanic acid is a versatile intermediate in ß–lactam

antibiotics synthesis

N

S

OCOOBn

TrHN H

COOH

H2N NH

S COOBnH

COOH

TrHN NH

S COOBnH

N

S

OCOOH

H2N H

Ph3CCl, Et2NH

N C N

67%

1) H2, Pd/C2) HCl aq

6-Aminopenicillanic acid

Penicillin amidase (1-2 kg), ammonia (0.09 kg), water (2 kg) Price ca. 1 USD/kg

N

S

COOH

HN

OPh

O

H

N

S

COOH

N

ClPh

O

H

N

S

COOH

H2N

O

H

Penicilin G

6-APA

1) TMSCl, CH2Cl22) PCl5, PhNMe2, CH2Cl2

NH3, n-BuOHPen acylase,NH3, water

Rozzell J. D.: Bioorg. Med. Chem. 1999, 2253

ß-lactam antibiotics

Penicillin V widely used due to stability permitting peroral application

N

S

COOH

H2N

O

H

6-APA

R1R2CHCOCl orR1R2CHCOOH, DCC

N

S

COOH

HN

OR1

O

HR2

R1 = Ph, R2 = H Penicillin G R1 = OPh, R2 = H Penicillin V R1 = Ph, R2 = NH2 Ampicillin R1 = 4-HO-Ph, R2 = NH2 Amoxycillin

Prodrugs

• chemical

- type of bond (ester, carbamate, ...)

- bioprecursors

- macromolecular prodrugs

Chemical release (activation of a prodrug) is advantageous in that it is not influenced by biological variability (as might be the case with enzymatic processes)

• mechanism of drug release

- enzymatic

- chemical (release triggered by physiological pH, while prodrug is stable eg. at lower pH 3-4)

Prodrugs/ß-lactam antibiotics

Ampicillin R = H

Pivampicillin R = -CH2-O-CO-t-Bu

Bacampicillin R = -CH(Me)-O-CO-O-Et

Talampicillin R = O

O

N

S

COOR

HN

O

NH2

O

H

Double ester prodrugs

DG O O R2

O OR1

DG O OH

O R1

DG OH O

O R1

R2

O

HO+

+

enzyme

Antibiotics

Penicillins - ß-lactam condensed with thiazolidin; Cephalosporins and cephamycins - ß-lactam condensed with

dihydrothiazines, more resistent to ß-lactamase; Penems - ß-lactam condensed with oxazolidines.

R1 = 4-py-SCH2, R2 = H, R3 = CH2OAc Cephapirin R1 = Ph, R2 = NH2, R3 = CH3 Cephalexin R1 = 4-HO-Ph, R2 = NH2, R3 = CH3 Cefadroxil R1 = Ph, R2 = NH2, R3 = Cl Cefaclor

N

HN

OR1

O

HR2

S

COOHR3

N

HN

OO

HS

COOH

-OOC

NH3+ OAc

Cephalosporin C Cephamycins

N

HNR1

OO

HS

COOHR2

OMe

N

O

COOHO

HOH

Clavulanic acid strong inhibitor of ß-lactamase,

used in combination with other types

Cephalosporins Synthesis

From cephalosporin C by a process similar to penicillins

From penicillins-S-oxides by a Pummerer rearrangement (Morin reaction)

N

S

COOMe

HN

OR1

O

HR2

O

N

HN

OR1

O

HR2

S

COOMe

N

HN

OR1

O

HR2

S

COOH

Ac2O

OAc

1) Base2) Hydrolysis

N

HN

OO

HS

COOH

-OOC

NH3+ OAc N

H2N

O

HS

COOH

OAc

cephalosporin-amidase

N

HN

O

HS

COOH

OAc

R

O

R-COX

N

HN

OO

HNH2

S

COOHHO

COOH

HN

HO

COOMe1) EtOCOCl, Et3N

2)

N

H2N

O

HS

COOH

hydrogenolysispossible on Pd/BaSO4

Production of penicillins from mould cultures more economical Sulfoxide by using sodium periodate in dioxane

Strategies and methods

isolation of active compound from natural sources bioassay-guided fractination of an extract natural product as lead/active compound (Mother Nature) structural optimization by chemical modification (Danishefsky, Nicolaou, …) by combinatorial chemistry (growth of productivity hasn´t materialized) large libraries for high-throughput/capacity screens shift to smaller libraries, eg. diversity oriented synthesis Origin of active compound (series of similar compounds) based on knowledge/study of the original natural product based on knowledge/study of initial hit/lead compound (even if the final product bears little to no resemblance to starting compound)

Bis-indoles in cancer treatment: Vinblastine and vincristine

Vin(caleuko)blastine, VLB approved 1965 (FDA) sulfate: 29*060-LE, Exal, Velban, Velbe antineoplastic agent „dimeric“ indole alkaloid Catharanthus roseus (Vinca r.) 1000 mg/1000 kg dried material

N

COOMe

OHN

HOAcEt

HNH

N

MeOOC

H

OH

MeO

20´14́

16́ N

COOMe

OHN

HCHO

OAcEt

HNH

N

MeOOC

H

OH

MeO

20´14´

16´

Vincristine (leurocristine, VCR, LCR) approved 1963 (FDA) sulfate: Kyocristine, Oncovin,

Vincrex antineoplastic agent „dimeric“ indole alkaloid Catharanthus roseus (Vinca r.) 20 mg/1000 kg dried material

Partial synthesis of (anhydro)vinblastine

N

COOMe

OHN

HOAcEt

HNH

N

MeOOC

H

OH

MeO

20´14́

16́

NH

N

COOMeEt

NH

N

COOMeEt

O

NH

N

COOMeEt

OCOCF3

NH

N

COOMeEt

Catharanthine

N

COOMe

OHN

HOAcEt

H

MeO

Vindoline

Vinblastine (3)2a2b 16´-epi

m-CPBA

1a1b 16´-epi

NH

N

COOMeVin

Et

H16´

15´

21´

TFAA

NaBH4

N

COOMe

OHN

HOAcEt

HNH

N

MeOOC

H

MeO

20´14´

16´

Potier P. et al: J. Am. Chem. Soc. 1976, 98, 7017. Potier P.: J. Nat. Prod. 1980, 43, 72.

Vindesine

Vindesine, VDS approved 1979 (FDA) sulfate: LY-099094, Eldisine, Fildesin antitumor agent, antineoplastic derived form„dimeric“ indole alkaloid

N

CONH2

OHN

HOHEt

HNH

N

MeOOC

H

OH

MeO

20´14́

16́

Vinorelbine and vinflunine

Vinorelbine approved 1989 ditartrate: Eunades, Navelbine antineoplastic agent derived form„dimeric“ indole alkaloid

Vinflunine clinical trials in Europe ditartrate: Javlor antineoplastic agent derived from„dimeric“ indole alkaloid

N

COOMe

OHN

HOAcEt

HNH

N

MeOOC

H

MeO

20´14´

16´ N

COOMe

OHN

HOAcEt

HNH

N

MeOOC

H

MeO

20´14´

16´

F F

Vinorelbine Vinorelbine Partial synthesis from anhydrovinblastine Potier-Polonovski reaction

N

COOMe

OHN

H OAcEt

HNH

N

MeOOC

H

MeO

20´14´

16´

N

COOMe

OHN

H OAcEt

HNH

N

MeOOC

H

MeO

20´14´

16´

NH

N

MeOOC

H

Vin

20´14´

16´

O

m-CPBA

NH

HN

MeOOC

Et

H

Vin

20´14´

16´

TFAA NH

N

MeOOC

Et

H

Vin

20´14´

16´

O

CF3

OF3CCOO-

NH

N

MeOOC

Et

H

Vin

20´14´

16´THF,H2O

Bis-indole alkaloids in future

X-ray of vinblastine – tubulin complex structure-based drug design total synthesis at best 12 steps partial synthesis from (-)-vindoline and (+)-catharanthine still prefered

NH

N

COOMeEt

Catharanthine

N

COOMe

OHN

HOAcEt

H

MeO

N

COOMe

OHN

HOAcEt

HNH

N

MeOOCH2

H

OH

MeO

20´14́

16́+

1) FeCl3, CF3CH2OH,0.1 N HCl aq, 23 °C 2 h

2) Fe2(ox)3/O2, then NaBH40 °C 30 min

ß-OH Vinblastine 41%α-OH Leurosidine 20%+ anhydrovinblastine 19%

Boger D. L. et al: J. Am. Chem. Soc. 2009, 131, 4904.

Paclitaxel

Taxol, Anzatax, Paxene, NSC-125973 studies started at NCI in 1950s approved 1993 antineoplastic agent, antirestenotic Pacific yew tree (Taxus brevifolia) trunk bark 0.02% = 2500 trees/1 kg other Taxus specii much lesser content partial synthesis? total synthesis?

ONH

OH

OH

OH

AcO

O

H

OAc

H

O

O

O

O

O

Paclitaxel – partial synthesis

OH

OH

HO

O

H

OAc

H

OCOPh

O

HO

OSiEt3

OH

AcO

O

H

OAc

H

OCOPh

O

HO

ONH

OPG

PhOC

OSiEt3

OH

AcO

O

H

OAc

H

OCOPh

O

O

COOHNH

OPG

PhOC

1) Protection at C(7)2) Acetylation at C(10)-OH

Esterification at C(13)-OH

ONH

OH

PhOC

OH

OH

AcO

O

H

OAc

H

OCOPh

O

O

10-Deacetylbaccatin III

Deprotection

13

107 7

77

10

1010

13

1313

Potier P., et al.: Acc. Chem. Res. 1993, 26, 160

yew tree Taxus baccata (Europe) 10-deacetylbaccatin III the most abundant (leaves 0.1%) synthesized at ICSN/CNRS (France) and by others

Paclitaxel – partial synthesis Potier P., et al.: Acc. Chem. Rev. 2011, 111, 7652

stereoview

Taxotere

derived from natural precursor synthesized at ICSN/CNRS (France) antineoplastic agent

Potier P., et al.: Acc. Chem. Res. 1993, 26, 160

OH

OH

HO

O

H

OAc

H

OCOPh

O

HO COOHNH

OPG

Boc

1) Protection at C(7)-OH andC-(10)-OH2) Esterification at C-(13)-OH

10-Deacetylbaccatin III1) Deprotection2) Acetylation

13

107

ONH

OPG

OCO2CH2CCl3

OH

Cl3CH2CO2CO

O

H

OAc

H

OCOPh

O

O

O

O

ONH

OH

OH

OH

AcO

O

H

OAc

H

O

O

O

O

O

O

10

10

13

13

7

7

Paclitaxel

paclitaxel nanoparticles approved 2005 paclitaxel poliglumex ester with homopolymer of L-glutamic acid

ONH

O

PhOC

O

NH

HN

COOH

HN

O

O

COOH

O

OH

OH

AcO

O

H

OAc

H

OCOPh

O

O

m n

API Medicine 2005 2006 2007 Paclitaxel Taxol (B-M S) 747 563 422 Paclitaxel nano Abraxane (Abraxis+AZ) 134 193 387 Taxotere Taxotere (S-A) 2.206 2.402 2.569

Sales in millions USD

Paclitaxel prodrugs

TaxN

O

R2

N

OTrip

R1

OTax

N

O

R2

NH

R1

O

N

N

O

R1

R2

plasmin

NH

O

OHO

OAcO O

OHO O OAc

OH

H

H

OTax-OH

History of orlistat (tetrahydrolipstatin)

lipstatin produced by fermentation tetrahydrolipstatin as anti-obesity drug (approved by FDA) biological activity based on reactivity of β–lactone moiety sibutramin and rimonabant both recently withdrawn made by semisynthesis

OOO

O

HN

CHO

OOO

O

HN

CHO

Synthesis of (-)-orlistat - temporary P-tether Hanson P. R. et al.: Org. Lett. 2010, 12, 1556.

Role of phosphorus as the phosphate:

• tether in RCM

• leaving group in SN2´ reaction • diol protection

OOO

O

HN

CHO

O OPO

OOH OH

Synthesis of (-)-orlistat - temporary P-tether Hanson P. R. et al.: Org. Lett. 2010, 12, 1556.

Role of phosphorus as the phosphate:

• tether in RCM • leaving group in SN2´ reaction

• diol protection

O OPO

O

n-H19C9

H-G Ru2g (10 mol%),DCM, rfl 2 hn-H19C9

85%

H

O OPO

O

n-H23C11 72%

o-NBSH, Et3N,DCM, rt 24 h

H

"one-pot"53%

"one-pot"40%

OH OH O OPi-Pr2N

PNi-Pr2

O OO

(S,S)-diol

(C2-symmetry)

1H-tetrazole,MeCN, rt 2 h,thenm-MCPBA, 1 h

64%

OO OP

O

O OPO

OG Ru2g (3 mol%),DCM, rfl

(S,S,PS)

85-90%H

O OPO

O

n-H23C11 Hn-H23C11

O OPOMe

O1) n-H13C6Li, CuCN.2LiCl,THF2) TMSCHN2, MeOH

65%

Single diastereoisomern-C6H11

H

O OPO

O

n-H23C11 H "Cuprate"

O OPO

O

n-H23C11 H "Cuprate"

Synthesis of (-)-orlistat - temporary P-tether Hanson P. R. et al.: Org. Lett. 2010, 12, 1556.

n-C6H13CuLi addition (anti-SN2´ pathway)

Role of phosphorus as the phosphate: • tether in RCM

• leaving group in SN2´ reaction • diol protection

n-H23C11

O OPOMe

O

n-C6H11H

n-H23C11COOH

O OH

n-C6H11

1) LiAlH4 (2 eq) [86%]2) TIPSOTf, 2,6-lutidine, -78 °C [80%]3) O3,-78 °C, Me2S; then NaClO2 [93%]

TIPS

n-H23C11

OO

n-C6H13

OO

i-BuHN

CHO

n-H23C11

OOH

n-C6H13

O

1) BOPCl, Et3N [82%]2) HF.py, THF [96%]

COOH

i-BuHN

CHO

DIAD, PPh3 [94%]

Synthesis of (-)-orlistat - temporary P-tether Hanson P. R. et al.: Org. Lett. 2010, 12, 1556.

Further medicines based on NP

hormones, steroids prostaglandins/prostanoids macrolides statins triptans ……..

Usage of natural products 1/2

natural products as drugs natural products as intermediates for synthesis of NP drugs natural products as starting materials for synthesis of modified NP drugs total synthesis of natural product drug when NP is not available in sufficient amount

Usage of natural products 2/2

Ecteinascidine 743/Trabectedin (Yondelis) from caribbean tunicate/pláštěnec Ecteinascidia turbinata powerful antitumor agent (antiproliferative activity) unique mechanism of action insufficient quantity even for clinical trials structurally related to saframycin class of antibiotics total synthesis Phthalascidin, Pt-650 synthesis of equipotent, simpler analogue

Cuevas C., Francesch A.: Nat. Prod. Rep. 2009, 26, 322. Avendano C., de la Cuesta E.: Chem. Eur. J. 2010, 16, 9722

NN

OH

H

H

HOOMe

AcO

OO

H

OSO

NH

HO

MeO

NN

CN

H

H

HOOMe

AcO

OO

H

NPhth

Ecteinascidine 743: Total synthesis

1st generation approach Corey E. J., et all.: J. Am. Chem. Soc. 1996, 118, 9202. 2nd generation synthesis Corey E. J., et all.: Org. Lett. 2000, 2, 993; Proc. Natl. Acad. Sci. U.S.A. 999, 96, 3496. multiple application of Pictet-Spengler processes partial synthesis from cyanosafracin B further total syntheses Fukuyama T., et al.: J. Am. Chem. Soc. 2002, 124, 6552 (50 steps, 0.56%) Zhu J.-P., et al.: J. Am. Chem. Soc. 2006, 128, 87 (31 steps, 1.7%) formal total syntheses Danishefsky S. J., et al.: Angew. Chem. Int. Ed. 2006, 45, 1754. Williams R. M., et al.: J. Org. Chem. 2008, 73, 9594.

NN

OH

H

H

HOOMe

AcO

OO

H

OSO

NH

HO

MeO

C = N double bond chemistry Addidion of various nucleophiles to C = N double bonds β–Aminocarbonyl compounds from carbonyl compounds and amines.

R2≠H immonium

R2=H iminium

R2=Ac N-acyliminium

Nu = 2-oxoalkyl Mannich

Nu = aryl Pictet-Spengler

Nu = CN α-Cyano amines

Nu = OR, NR2

Nu = H N

R

R1RNR

R1R

NuNu

NR

R1

R2N

R

R1

R2

RRNR

R1

R2

R

Nu

NuH

NR

R1R

[R2=H]

OR

R

HNR2

R1

Mannich processes

Mannich reaction Synthesis of β–aminocarbonyl compounds from carbonyl compounds and amines

NR2R3

R4

R1OR2

R1 HNR4

R3

OR6

R5 R5

R6

O

NR2

R3

R4

R1

OR6

R5

H

+

Pictet-Spengler processes

Pictet-Spengler reaction Tetrahydroisoquinolines (or tetrahydro-β-carbolines) from 2-arylethylamines and carbonyl compounds

HNR

O

R2

R1 NR

R1 R2

NR

R2

R1

[R2 = H]

OHN

X

Y N

X

Y N

X

Y N

XY

H+

X = Y = H2 No reaction

N-Acyliminium variant of Pictet-Spengler cyclization

Ecteinascidine 743: total synthesis

1st generation approach Corey E. J., et all.: J. Am. Chem. Soc. 1996, 118, 9202. long synthesis to provide sufficient material for clinical tests 32 steps from sesamol in the longest linear sequence enantio- and stereocontrolled, convergent

NN

OH

H

H

HOOMe

AcO

OO

H

OSO

NH

HO

MeO

Ecteinascidine 743: 1st total synthesis 1/2

HO2C

OBn

OO

O

O

OMeOMe

NH

OBn

OO

O

OH

CbzOMe

OMe

Reagents and conditions a) BF3.OEt2 (10 eq), H2O (10 eq), CH2Cl2. b) BF3.OEt2 (17 eq), 4A MS, CH2Cl2 (73%). c) H2 (1 atm), 10% Pd/C, AcOEt (100%). d) KCN (25 eq.), AcOH. e) CH2=CHCH2Br (5 eq.), Cs2CO3 (2 eq.), DMF (87%). f) Dibal-H (1.2 eq), PhMe, -78 °C. g) KF.2H2O (excess), MeOH. h) MsOH (20 eq), 3A MS, CH2Cl2 (55%).

NN

CN

H

H

HOOMe

OHOAll

OO

HN COOAll

N

OAll

OO CN

TBSOOMe

OTBS

H

HOOH

f - h

C

N

OH

OO

O

O

HCbzN

OBn

OO

O

OH

a, b c

HA

HN COOAllN

OAll

OO

O

O

CN

TBSOOMe

OTBS

H

d, eOHC

HN

O

O

OMeTBSO OTBS

B

Ecteinascidine 743: 1st total synthesis 2/2

NN

CN

H

H

OOMe

AcO

OO

H

MOM

OS

NHHAllO2C

O

NN

CN

H

H

OOMe

O

OO

H

MOM

O

SONHCOOAll

a

NN

CN

H

H

OOMe

AcO

OO

H

MOM

OSO

O

NN

OH

H

H

HOOMe

AcO

OO

H

OSO

NH

HO

MeO

b, cd - f

NH2

HO

MeO

Reagents and conditions: a) Tf2O, DMSO, -40 °C, then iPr2NEt, then t-BuOH, (Me2N)2C=NtBu, then Ac2O (79% overall). b) (Ph3P)2PdCl2 (cat), Bu3SnH (excess), AcOH (84%). c) (4-Formyl-1-methylpyridinium iodide (20 eq), DBU (20 eq), DMF (70%). d) (3-Hydroxy-4-methoxyphenyl)ethylamine, silica gel, EtOH (82%). e) TFA/THF/H2O (4:1:1). f) AgNO3 (20 eq), MeCN/H2O (3:2), CH2Cl2, 23 °C 11 h (77%).

NN

CN

H

H

OOMe

O

OO

HOH

MOM

O

S FlONHCOOAll

NN

CN

H

H

MOMOOMe

OH

OO

H

OTBDPS

Ecteinascidine 743: Improved total synthesis

2nd generation synthesis Corey E. J., et all.: Org. Lett. 2000, 2, 993; Proc. Natl. Acad. Sci. U.S.A. 1999, 96,

3496. more efficient intermediate C synthesis yield improved from 35% to 57% over 6 synthetic steps synthesis still not suitable for manufacturing

N

OH

OO

O

O

H

H

A

OHC

HN

O

O

OMeTBSO OTBS

B

NN

CN

H

H

HOOMe

OHOAll

OO

H

OHC

+

Ecteinascidine 743: Partial synthesis From cyanosafracin B (PharmaMar), Trabectedin (Yondelis) Cuevas C., et all.: Org. Lett. 2000, 2, 2545. Cyanosafracin B, an antibiotic produced by fermentation from the bacteria Pseudomonas fluorescens short and straightforward process amenable to production in economical way

NN

CN

H

H

HOOMe

OH

NHO

MeO

ONH2

NN

CN

H

H

MOMOOMe

OAll

OO

H

OH

NN

CN

H

H

MOMOOMe

OAll

OO

H

NH2NaNO2,AcOH 50%

NN

CN

H

H

MOMOOMe

OHH

NBoc

ONH2

OO

D

Phthalascidin: Partial synthesis From cyanosafracin B (PharmaMar) Cuevas C., et all.: Org. Lett. 2000, 2, 2545. original synthesis Corey E. J., et all.: Org. Lett. 1999, 1, 75; ibid. 2000, 2, 993; Proc. Natl. Acad. Sci.

U.S.A. 1999, 96, 3496.

NN

CN

H

H

HOOMe

AcO

OO

H

NN

CN

H

H

MOMOOMe

OHH

NBoc

ONH2

NO O

NN

CN

H

H

HOOMe

AcO

OO

H

NH2

OO

1) AcCl (100%)2) TFA (60%)3) PhNCS (63%)

4) HCl/dioxane(87%)

D

Pht2O,CDI

(93%)

Classification of drugs

Categories B Biological agent usually a large peptide or protein; isolated from organism or made by

biotechnology N Natural product ND Derived from natural product a modification of natural product, by partial synthesis S Totally synthetic drug often a result of a random screening/modification of an existing drug S* Totally synthetic drug as above but: pharmacophore (active skeleton) is from natural product

Subcategory NM Natural product mimic S/NM, S*/NM

David J. Newman; Gordon M. Cragg; J. Nat. Prod. 2007, 70, 461, 2003, 66, 1022.

Natural product mimic

direct inhibitors/antagonists of the natural substrate/receptor

interaction obtained by direct experiment obtained by studies in silico followed by direct assay in the relevant system peptidic drugs often by synthesis rather than by bioprocesses peptide isosteres, pseudopeptides (peptidomimetics) = NM protein tyrosine kinase inhibitors as example imatinib considered as a breakthrough in the treatment of leukemia

David J. Newman; Gordon M. Cragg; J. Nat. Prod. 2007, 70, 461, 2003, 66, 1022.

Imatinib

PTK inhibitor mesylate: Gleevec/Glivec approved 2001 (Novartis) treatment of leukemia

N

N

N

NH

NH

O

NN

Inib family

Sunitinib 2006

N

N

N

NH

NH

O

NN

API Medicine 2005 2006 2007

Imatinib mesylate Gleevec 2.170 2.554 3.050

Erlotinib HCl Tarceva (Roche, Genentech, Chugai, …) 408 833 1.054

Sunitinib malate Sutent (Pfizer) 0 219 581

Gefitinib Iressa (AZ) 273 237 238

Sales in millions USD

Erlotinib 2004

Gefitinib 2003

MeOMeO

O

O

HN

N

N

CN NH

NH

NH

NEt2

OF

O

O

MeO

HN

N

N

Cl

F

NO

New products 01/1981–06/2006

Total number: 1184 entities

David J. Newman; Gordon M. Cragg; J. Nat. Prod. 2007, 70, 461-477.

Copyright © 2007 American Chemical Society and American Society of Pharmacognosy

New products 01/1981–06/2006

Total number: 1184 entities

David J. Newman; Gordon M. Cragg; J. Nat. Prod. 2007, 70, 461-477.

Copyright © 2007 American Chemical Society and American Society of Pharmacognosy

New small moleculess 01/1981–06/2006

Total number: 974 entities

David J. Newman; Gordon M. Cragg; J. Nat. Prod. 2007, 70, 461-477.

Copyright © 2007 American Chemical Society and American Society of Pharmacognosy

New small moleculess 01/1981–06/2006

Total number: 974 entities

David J. Newman; Gordon M. Cragg; J. Nat. Prod. 2007, 70, 461-477.

Copyright © 2007 American Chemical Society and American Society of Pharmacognosy

New anticancer drugs 1940s–06/2006

Total number: 175 entities

David J. Newman; Gordon M. Cragg; J. Nat. Prod. 2007, 70, 461-477.

Copyright © 2007 American Chemical Society and American Society of Pharmacognosy

New anticancer drugs 1950–06/2006

Total number: 157 entities with known dates

David J. Newman; Gordon M. Cragg; J. Nat. Prod. 2007, 70, 461-477.

Copyright © 2007 American Chemical Society and American Society of Pharmacognosy

Threat and prospect

Samuel M. Danishefsky: „Thus, the decision on the part of several pharma companies to get out of the natural products business is gross foolishness. There are major teachings in these natural products that we would do well to consider. They may be reflecting eons of wisdom and refinement. The much maligned natural products collections did, after all, bring us to statin, ß-lactam, aminoglycoside, and macrolide blockbuster drugs. In fact, one of the most promising approaches in diversity chemistry is to produce diversity-chemistry-derived collections that benefit from or partake of the ‘wisdom’ of natural products. “ (Chem. Eng. News 2002, 80 (2), 23-24)

Dennis Pirages

„infectious diseases are potentially the largest threat to human security lurking in the post-cold war world“ (Wash. Quart. 1995, 18, 5-12)

Future of natural products

Dennis Pirages

„urgent need to identify novel, active chemotypes as leads for effective drug development“ (J. Nat. Prod. 2007, 70, 461-477)

Living organisms proved to be the prime source of such lead discoveries, cf. the discovery of „wonder“ antibiotics in the 1940´s and 1950´s.

Norman R. Farnsworth:

„The world of plants represents a virtually untapped reservoir of novel drugs awaiting imaginative and progressive organizations“

(Pharm. Technol. 1995 (Aug), 14-15)

All living organisms