Term
| general MOA of natural compound as anticancer agents |
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Definition
many of the naturally occurring anticancer compounds have antibiotic activity in addition to the anticancer activity
MAY INTERCALATE BETWEEN THE BASE PAIRS OF DNA
strong non-covalent bones
deforms and uncoils DNA
prevents proper replication
affects the action of many associated proteins
MAY INHIBIT TOPOISOMERASE I OR II
enzyme that is involved in cleavage of DNA during replication, but repairs cleavage after replication
topoisomerases are enzymes that cause transient strand breakage during transcription
MAY GENERATE CYTOTOXIC FREE RADICALS THAT BREAK DNA STRAND
MAY TARGET TUBULIN AND MICROTUBULES (ANTIMIOTIC) |
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Term
| compounds that generate radicals |
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Definition
antracyclines (streptomyces): daunorubicin and doxorubicin
actomycins (streptomyces): dactinomycin
bleomycins (streptomyces verticullus): bleomycin sulfate
these compound may generate radicals which can break DNA strands
actinomycins are derived from streptomyces strain and have the ability to generate radicals due to a chromophore in their structure known as a quinoneimine
reduction of this quinoneimine can lead to radical generation
bleomycins chelate Fe++ and generate radicals |
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Term
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Definition
antracyclines
actinomycins
they have a planar compound to their structure that allows DNA intercalation |
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Term
| bifunctional alkylating agents |
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Definition
mitomycins: mitomycin c
mitomycin C is bioactivated to a species that can serve as a bifunctional alkylating agent |
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Term
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Definition
taxanes (pacific yew): paclitaxel (Taxol)
epothilones: epothilone B
the taxanes, and epothilones stabilize microtubulin
as a result, they act as antimitotic agents |
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Term
| inhibition of tubulin polymerization |
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Definition
vinca alkaloids: vincristine and vinblastine
eribulin
the vinca alkaloids bind to microtubules causing depolymerization
eribulin inhibits microtubule dynamics in a novel mannar
the compound binds to an unique site on tubulin resulting in suppression of microtubulin polymerization without effects on depolymerization
also, it sequesters tubulin into non-functional aggregates
by inhibiting miotic spindle formation, eribulin causes irreversible mitotic block, which ultimately leads to cell cycle arrest in the G2-M phase and apoptosis |
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Term
| topoisomerase II inhibitors |
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Definition
anthracyclines (intercalators): doxorubicin
epipodophyllotoxins (American Mandrake or Mayapple): etoposide
topoisomerases play a role in DNA replication and trascritpion
the taxanes and epothilones inhibit topoisomerase II leading to double strand breaks |
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Term
| topoisomerase I inhibitors |
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Definition
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Term
| anticancer agents acting via radical species |
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Definition
ANTRHACYCLINES:
doxorubicin
daunorubicin
idarubicin
epirubicin
valrubicin
ANTRACENEDIONES:
mitoxanthrone
ACTINOMYCINS:
dactinomycin
BLEOMYCINS:
bleomycin sulfate |
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Term
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Definition
radical-chemical species capable of independent existence with one or more unpaired electrons
[image]
radicals are independent chemical species that have one or more unpaired electrons
the superoxide radical is generated by the 1 electron reduction of molecular oxygen
superoxide dismutase can convert superoxide to O-2, which can form hydrogen peroxide in the presence of 2H+
hydrogen peroxide can be broken to yield hydroxyl radicals
also, hydrogen peroxide, in the presence of Fe++, can form hydroxyl radicals
the enzyme catalase will break hydrogen peroxide down to water and oxygen
although radicals are desirable to treat cancer cells (cleavage of DNA strands), they can be harmful to normal tissue |
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Term
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Definition
[image]
[image]
ANTHRACYCLINES ARE GLYCOSIDES
the non sugar is the AGLYCONE - anthracyclinone
the SUGAR is L-daunosamine
anthracyclines consits of a non-carbohydrate portion (aglycone) and a carbohydrate portion (L-daunosamine) connected via a glycosidic linkage
the sugar is L- the substituent down at position C5
the aglycone portion of the antracyclines is known as anthracyclinone
QUINONE MOIETY: highly oxidized state and is subject to reduction; compounds that contain quinones undergo one electron reductions to form radicals
[image]
doxorubicin differs from the other antracyclines in having a COCH2OH group instead of CH3 at position 9
valrubicin has a lipophilic ester attached to the OH at C9 that enhances its lipophilicity
additionally the trifluoroacetyl group enhances its lipophilicity
rubicin = red
idarubicin is lacking a substituent on position 4
epirubicin is an epimer - the sugar OH is beta instead of alpha
both the aglycone and the sugar is necessary for activity
amino sugars (4 of the above) is important for activity (intercalation into DNA) b/c it will inize at pH 7.4 and the + will interact with phosphate in the DNA backbone
[image]
the aglycone portion is essentially planar and readily intercalates DNA
aglycone is planar and the amino sugar is below to help stabilize the binding in its protonated form (interaction with the posphate of DNA) |
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Term
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Definition
intercalate into DNA
poisoning of topoisomerase II
generation of oxygen free radicals (-OH, O2--, and H2O2) |
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Term
| metabolism of anthracyclines |
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Definition
[image]
the carbonyl group on the side chain at C9 can be reduced by aldo-keto reductases
the resulting alcohol is active, but it is taken up more slowly by cancer cells (more polar)
some of the ADRs may be attributed to the OH metabolite
cleavage of the glycosidic clinkage by glycosidases results in formation of the aglycone
INACTIVE species (the amino sugar is not assisting in binding to DNA)
the species can be demethylated at C4 and conjugated as the water soluble sulfate conjugate (inactive) |
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Term
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Definition
[image]
valerate ester enhances entry into cancer cells due to increased lipophilicity
CF3 electron withdrawing but lipid enhancing
orphan drug (used for intravesicular therapy) refractory bladder cancer
little systemic absorption and the drug is excreted essentially unchanged
the trifluoroacetyl group masks the amino group of the sugar and increases its overall lipophilicity |
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Term
| antracyclines: generation of semi-quinone radical |
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Definition
[image]
antracyclines can generate radicals by a one reduction to give a semi-quinone radical
in the presence of O2, the semiquinone radical can be oxidized to the quinone and generate superoxide radical in the process
CHELATING ABILITY IS AN IMPORTANT CHEMICAL PROPERTY RELATED TO THE ANTICANCER ACTIVITY OF ANTHRACYCLINES
[image]
the chelating ability is an important chemical property of the antracyclines
oxidation of chelated Fe++ to Fe+++ by hydrogen peroxide can generate OH radicals which can fragment DNA
Fe2 oxidized to Fe3 = generation of hydroxyl radical |
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Term
| cardiotoxicity of antracyclines |
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Definition
[image]
the cardiotoxicity of the anthraquinones may be due to reduction to a hydroquinone followed by loss of the glycosidic linkage
the aglycone may be responsible for the cardiotoxicity of these compounds
LOW LEVELS OF CATALASE IN CARDIAC TISSUE
CARDIOTOXICITY IS ATTRIBUTED TO THE AGLYCONE FORM
[image]
generation of hydroxyl radicals is highly desirable in treatment of cancer cells
however, the heart lacks catalase and therefore the highly toxic hydroxyl radical is generated
the aglycone can generate superoxide radicals upon reduction to the hydroquinone
the enzyme superoxide dimutase in the presence of Cu++ can generate hydrogen peroxide
in the presence of Fe++, hydrogen peroxide can oxidize the iron to Fe+++ and produce hydroxyl radicals
in normal tissue, catalase can act on hydrogen peroxide to yield water and oxygen
however, in cardiac tissue, there is low level of catalase
as a result, these radicals (hydroxyl and superoxide) are highly toxic to cardiac tissue |
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Term
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Definition
[image]
contains structural feature necessary to intercalate DNA (note the relatively planar anthracenedione nucleus)
chemically, mitoxantrone is an anthracenedione
note that the terminal ring is missing in comparison with anthracyclines
it has the necessary planar structure to intercalate DNA
anthracenedione has the quinone moiety!
the difference is that it does not have an amino sugar, but DOES have an amino side chain
does not have a terminal ring - implies that the terminal ring is not required for activity
intercalates - ring system is planar and the amino group is protonated and interacts with the phosphate backbone of DNA |
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Term
| structural comparison of mitoxanthrone and antracyclines |
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Definition
[image]
anthracyclines and anthracenediones:
intercalate DNA (planar structures)
generate radicals (hydroxyl, superoxide, and hydrogen peroxide)
topoisomerase II poison
although mitoxanthrone does not contain an amino sugar unit, the terminal amino nitrogen on the side chain matches up with the amino group on the amino sugar of the antracyclines
note the triangle formed among the carbonyl, hydroxyl, and side chain nitrogen in both compounds
[image]
reduction of the side chain carbonyl may produce some of the chronic cardiotoxicity associated with the antracyclines
mitoxanthrone lacks a side chain carbonyl and is less cardiotoxic
the chronic toxicity of the anthracyclines may be due in part to reduction of the side chain carbonyl at C9 to the alcohol metabolite
since mitoxanthrone lacks this carbonyl group, it is less toxic |
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Term
| metabolism of mitoxanthrone |
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Definition
[image]
the metabolism of mitoxanthrone is shown above
it undergoes N dealkylation to form a primary amine
this substance can then undergo oxidative deamination by P450 to yield an aldehyde
the aldehyde can be further oxidized by aldehyde dehydrogenase to the inactive carboxylic acid |
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Term
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Definition
actinomycins are a group of closely related structures which contain the same chromophore
3-phenoxazone-1,9-dicarboxylic acid
[image]
highly conjugated system that incorporates an imino-quinone like moiety
3 phenoxazone ring system is planar so it could intercalate into DNA
no quinones in this structure but there is a carbonyl and a C=N opposite - this can generate radicals through one electron reduction |
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Term
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Definition
[image]
SAR:
1. opening of lactone ring decreases activity
2. change in stereochemistry decreases activity
3. replacement of the 4-Me and 6-me groups on the phenoxazone ring decreases activity
4. replacement of the 2-NH2 group decreases activity
attached to the carboxylic acid groups at the 1 and 9 positions (via amide linkages) are peptapeptide groups
the peptides contain several non-natural amino acids which makes them metabolically more stable to peptidase action
the peptide is attached to the 3-phenoxazone ring via a lactone linkage
this lactone group is formed from the carboxy group of L-Me Val and the side chain Thr residue
ring opening of this lactone decreases the activity of dactinomycin
this is b/c the peptide chain fits into the minor group in DNA
when the lactone is hydrolyzed it does not bind as well in the minor groove
substitution on the phenoxazone nucleus generally decreases activity
BE ABLE TO RECOGNIZE LACTONES (CYCLIC ESTERS) |
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Term
| radical generation by dactinomycin |
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Definition
[image]
the quinoneimine moiety in the 3-phenoxazone nucleus of dactinomycin can undergo a one electron reduction to form a semiquinone-imine radical
this radical can be oxidized back to the quinone imine to give off an electron
reaction of this electron with molecular oxygen can generate superoxide radical
this radical can result in DNA strand cleavage |
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Term
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Definition
generation of radicals
[image]
dactinomycin intercalates DNA adjacent to G-C bases
the polypeptide chains extend along the minor groove stabilizing the complex
main effects appears to be on topoisomerase II |
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Term
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Definition
[image]
bleomycin is actually a mixture of 2 compounds (bleomycin A2 and bleomycin B2)
there are several regions in its structure that are important
the metal binding portion of the structure contains several nitrogen atoms that can chelate Fe++
this region of the molecule is separated from the DNA binding domain by a tripeptide linking
the heterocyclic bases containing the side chains interact with DNA
note that bleomycin contains 2 glycosidic linkages
side chain is either a sulfonium or guanidinium - both are protonated and will interact with a phosphate on the DNA backbone
part of the structure of bleomycin involved in Fe++ chelation:
[image]
this is a representation of bleomycin binding molecular oxygen in the metal binding domain of the molecule
once bound Fe++ can generate radicals upon oxidation to Fe+++
bleomycin is inactivated by bleomycin hydrolase:
[image]
tumor cells deficient in bleomycin hydrolase will be more sensitive to bleomycin
hydrolysis of bleomycin by bleomycin hydrolase cleaves the terminal amide residue
once hydrolyzed the amino acid undergoes intramolecular H-bonding and removes a site of chelation with Fe++
thus, the compound is biologically inactive
H bonding site to the iron is removed |
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Term
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Definition
[image]
natually occurring antitumor agent (contains quinone and aziridine groups)
used in a variety of tumors (breast, stomach, esophagus, and bladder)
prototype of reductively activated alkylating agents
mitomycin C contains several reactive functional groups
the compound contains the 3 membered aziridine ring, a quinone group, and a side chain carbamate
we know that reduction of quinone functional groups can generate radicals
thus, some of the effects of mitomycin may be due to radical generation
[image]
3 things in terms of reactivity = quinone, aziridine ring (C adjacent to the aziridine ring subject to Nu attack), and the carbamate (C linkage is subject to alkylation)
mitomycin forms a reactive species capable of acting as a bifunctional alkylating agent
can bind to DNA and undergo oxidation-reduction to yield H2O2
this species can form highly reactive radicals that may cause strand cleavage of DNA
mitomycin C undergoes bireductive activation
as a result, the compound can serve as a bifunctional alkylating agent
bioactivation of mitomycin C:
[image]
the bioactivation of mitomycin begins with a 2 electron reduction to conver the quinone to a hydroquinone
this species then loses a molecule of methanol
the movement of electrons in this hydroquinone intermediate results in the opening of the aziridine ring
the 3 member ring is under considerable strain and this strain is alleviated by ring opening
a nucleophilic group on one of the purine or pyrimidine bases in DNA attacks the reactive intermediate to produce an alkylated DNA adduct
finally, the monoalkylated adduct is attacked by DNA to result in the loss of the carbamate group, leading to a bis-alkylated DNA adduct
DNA attached to the C adjacent to the carbamate and the carbon adjacent to the aziridine ring
summary of mitomycin C bioactivation and bifunctional alkylation
[image]
1. reduction of the quinone to the hydroquinone (radical generation is possible)
2. loss of methanol
3. opening of aziridine ring
4. attachment of a nucleophile on the 5 membered ring of mitomycin
5. attachment of a nucleophile on the carbon bearing the carbamate group
cross linking of DNA by mitomycin C
[image]
the cross links can be either interstrand or intrastrand |
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Term
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Definition
antracyclines and mitoxanthrone
dactinomycin
deforms DNA and leads to interference with DNA associated proteins (polymerases, transcription factors, DNA repair systems, and topoisomerases
DNA intercalating agents insert between the base pairs of DNA |
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Term
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Definition
nuclear enzymes that induce transient breaks in DNA allowing a single strand break or double strands to pass through each other
DNA replication
recombination of strands
condenstation-decondensation of chromosomes
DNA topoisomerase are enzymes that play an important role in DNA replication and transcription
in the tertiary structure of DNA, the long DNA molecule must be compacted to fit into the nucleus
this process is termed supercoiling
supercoiling requires the action of DNA topoisomerases
these enzymes catalyze the act of one strand of DNA through another
this is achieved by cleaving one or both DNA strands
this results in a temporary gap that is resealed after crossover
uncoiling must occur for replication and transcription to take place
the unwinding of the strands are catalyzed by helicases
the same topoisomerase responsible for the coiling are responsible for the uncoiling process
thus, inhibition of topoisomerases would effectively block transcription and replication
topoisomerases bind a single or double strand of DNA where 2 regions of DNA are in proximity
topo II causes a break in both strands of DNA allowing the other segment of DNA to pass through this transient gap
after this occurs, the enzyme catalyzes the resealing of the double strands of DNA
if this process is inhibited by inhibition of topoisomerases, transcription and DNA replication is inhibited
DNA topoisomerases regulate the topology of DNA and are essential for transcription
topoisomerase I - DNA single strand breaks
topoisomerase II - DNA double strand breaks and requires ATP
[image]
the key cleavage of the DNA strand is the action of a side chain Tyr OH group on the 3' phosphate group
this is a reversible process
inhibitors of DNA topoisomerases prevent the re-ligation of the DNA strand, leading to fragmentation of DNA |
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Term
| topoisomerase II inhibitors |
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Definition
intercalators: anthracyclines and mitoxanthrone
[image]
non-intercalators: etoposide and related analogs |
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Term
| epipodophyllotoxins (glycosides): etoposide and related analogs |
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Definition
bind tubulin, but main effect is on topoisomerase II
stabilize the ternary complex (DNA, drug, and enzyme), thus preventing re-ligation
DNA fragments accumulate leading to apoptosis
RNA transcription is also inhibited
podophyllotoxin:
[image]
this compound is a LACTONE containing compound (many natural products have lactone rings)
the compounds that are used as anticancer agents are epimers of this compound at position 4
[image]
[image]
teniposide more potent than etoposide (note the presence of the 2-thienyl group in teniposide)
this facilitates entry into the cancer cell
both compounds are POORLY WATER SOLUBLE
these compounds are lactone glycosides
in the case of teniposide, the 2-thienyl group increases its lipophilicity and facilitates its entry into cancer cells
both compounds are poorly water soluble
the acetal group on the terminal sugar can be viewed as the reaction product between an aldehyde and the dihydroxy groups of D-glucose
etopophos: prodrug of etoposide
[image]
the phosphate ester enhances its water solubility
the compound is activated to etoposide by the action of phaophatases |
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Term
| metabolism of epipodophyllotoxins |
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Definition
[image]
inhibitors of CYP3A4 increase toxicity (azoles, macrolides)
inducers increase clearance (phenytoin, phenobarbital)
the metabolism of the epipodophyllotoxins is shown above
ring opening of the lactone group yields an inactive compound
additionally, CYP3A4 can catalyze the demethylation of the methyl ether to yield a caechol metabolite
the catechol can be further oxidized to a quinone
the quinone metabolite is an inhibitor of topoisomerase II
LACTONE RING IS ESSENTIAL FOR ACTIVITY TO PREVENT TOPO II
ortho quinone is also active and can inhibit topo II |
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Term
| topoisomerase I inhibitors |
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Definition
suppressors which inhibit the enzyme, but do not stabilize the DNA topoisomerase covalent complex
topoisomerase poisons - act after DNA cleavage and prevent religation |
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Term
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Definition
[image]
these compounds contain both lactam and lactone functional groups
[image]
the camptothecins differ in their substitution at R1, R2, or R2
note that topotecan or irinotecan contain basic side chains; this allows for salt formation increasing water solubility
all of the compounds contain a 6 membered lacton group
irinotecan is a carbamate prodrug |
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Term
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Definition
[image]
substitution is allowed in ring A at positions 9 and 10 and in ring B at position 7
the lactone is necessary for activity
the basic side chain increases the water solubility of these compounds
once the lactone ring is opened, it is no longer active |
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Term
| low water solubility issues of camptothecins |
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Definition
camptothecins have low water solubility
administered in large doses as a result and causes ring opening of the lactone
[image]
the hydroxy acid can close back to the lactone at the kidney pH
as a result, it achieves high concentrations in the kidney and can react with SH containing proteins to produce hemorrhagic cystitis
topotecan and irinotecan are more water soluble and don't accumulate in the kidneys |
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Term
| irinotecan used with 5FU first line therapy in treatment of metastatic colorectal cancer |
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Definition
[image]
irinotecan is actually a prodrug
the basic side chain increases its water solubuility
it then undergoes bioactivation by carboxylesterases to yield a phenol (topotecan) and a carbamic acid
the carbamic acid readily loses carbon dioxide to yield a diamine metabolite |
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Term
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Definition
[image]
1) conjugation with the phenol with beta-glucuronic acid
2) N-demethylation
3) ring opening of the lactone group to a hydroxy acid |
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Term
| binding of camptothecin and DNA and topoisomerase I |
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Definition
[image]
this shows a binding model of camptothecin at the active site of topoisomerase I
note that the lactone group interacts by ion-dipole attractions with the Arg 364
this is the reason that ring-opening leads to a loss of biological activity, H-bonding is impeded
IMPORTANCE OF THE LACTONE RING: complex if formed that is an inhibitor of topo I and also needed to bind to DNA
Arg 364 is very important in binding to the lactone group of camptothecin |
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Term
| tubulin - transport protein crucial to cell division |
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Definition
[image]
transport proteins are usually not a drug target; however, tubulin is the exception
tubulin is critical for cell division
tubulin polymerizes to give microtubules (small tubes) in the cell cytoplasm
they perform many functions including maintaining cell shape
when cells are about to divide, microtubules depolymerize to give tubulin
the tubulin then repolymerizes to form the spindle
this is a structure that serves to push the dividing cells apart and act as a framework in which the chromosomes of the original cell is transferred to the new cell
drugs that inhibit this process are effective anticancer agents
the taxanes (paclitaxel and docetaxel)accelerate polymerization and stabilize the microtubules
whereas, the vinca alkaloids inhibit polymerization
either way, drugs that affect with equilibrium produce a toxic effect and inhibit cell division
COMPOUNDS EXERT THEIR EFFECTS BY DISRUPTING THE TUBULIN EQUILIBRIUM:
BINDS TO TUBULIN AND INHIBITS POLYMERIZATION - VINCA ALKYLOIDS
BIND TO MICROTUBULES AND INHIBIT DEPOLYMERIZATION - TAXANES
microtubules are hollow structures composed of 13 parallel protofilaments composed of alpha and beta tubulin
tubulin dimers polymerize during mitotic spindle formation
the microtubules depolymerize during cell division
thus, this is a dynamic equilibrium
compounds can act on microtubules to stabilize or destabilize them or bind to tubulin to inhibit polymerization |
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Term
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Definition
[image]
the vinca alkaloids are found in the periwinkle plant
the complex molecules are described as alkaloids
that is, they are basic naturally occurring compounds
the upper ring contains the heterocycle indole and is designated as the catharanthine ring
the bottom ring contains an indoline ring and is designated vindoline
vincristing and vinblastine are vinca alkaloids
vinblastine is more lipophilic and better entry into cell
vinca alkaloids bind tubulin at high and low affinity sites
binding at the high affinity site affects both lengthening and shortening of the spindle, thereby affecting its function
binding at the low affinity site (at high drug concentration) leads to a breakdown of the spindle as tubulin depolymerizes)
the vinca alkaloids bind tubulin at sites different from the taxanes and the epithilones
at low concentrations of the drug, the vincas bind to the high affinity site and prevent lengthening and shortening of the miotic spindle
thus, the spindle function is disrupted
at high concentration, the vinca alkaloids cause the mitotic spindle to breakdown as tubulin depolymerizes |
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Term
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Definition
[image]
1) both rings are required for activity
2) the OH group at C4' can be replaced by a double bond.
3) the bridge between the indole ring in the catharanthine ring and the basic 6 membered ring can be 1 or 2 carbons
4) hydrolysis of the 4 acetate ester yields an active OH metabolite |
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Term
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Definition
[image]
vinorelbine and vinblastine are more lipophilic than vincristine and enter the cell more readily
both the catharanthine and vindoline components are required for activity
the presence of the methyl group on the indoline nitrogen increases lipophilicity of vinblastin and vinorelbine
this enhances their ability to pass through cell membranes |
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Term
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Definition
[image]
binds to unique site on tubulin
suppresses microtubule polymerization
causes irreversible miotic block leading to cycle arrest and apoptosis
does not effect depolymerization
also, it sequesters tubulin into nonfunctional aggregates
by inhibiting mitotic spindle formation, eribulin causes irreversible miotic block, which ultimately leads to cell cycle arrest in the G2-M phase and apoptosis
amine increases water solubility |
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Term
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Definition
[image]
trabetedin contains 2 fused tetrahydro isoquinoline rings linked by a benzylic sulfide that is attached to a third tetrahydroisoquinoline ring
in contrast to traditional alkylating agents that bind guanine at N7 or )6 positions, trabectedin binds the exocyclic amino group of guanine at the C2 position
this occurs in the minor groove of DNA
the resulting adduct is stabilized by van der waals interactions and one or more hydrogen bonds between trabectedin and the neighboring nucleotides in the strads of DNA, thus creating a functional crosslink
binding model of trabectedin in the minor groove of DNA:
[image]
after loss of OH, a reactive intermediate is formed
this species undergoes reaction with the C2 amino group of a guanine residue in the minor groove of DNA |
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Term
| taxanes (mitosis inhibitors) |
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Definition
microtubule stabilizing agents binding at the taxane site
the taxanes are diterpenes
these compounds are derived from 4 isoprenoid units to give a C20 skeleton
the pacific yew and the English yew are sources of taxanes
[image]
the English yew is a much better source of paclitaxel than the pacific yew
the compound 10-decaethylbaccatin III can be obtained from the English yew
this compound can be converted into paclitaxel or docetaxel by semi synthesis |
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Term
| SAR of taxol and related taxoids |
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Definition
[image]
northern half substitutions not that specific
southern half substitutions are important
3'N important for binding to tubulin
ester at 2' and OH has to be alpha |
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Term
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Definition
[image]
note that the tert-butyl group in docetaxel replaces a phenyl ring
this suggests that it is binding to some lipophilic site at its target site |
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Term
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Definition
[image]
a variety of metabolites are possible with paclitaxel
the major metabolite is the 6 alpha OH metabolite
hydroylsis of the acetate at C10 yields an active metabolite |
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Term
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Definition
[image]
docetaxel is hydroxylated by CYP3A4 on the methyl group of the tert-butyl group |
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Term
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Definition
[image]
binds to and stabilizes microtubules
prevents microtubule depolymerization and cell division
cabazitaxel used in combination with prednisone for metastatic castration-resistant prostate cancer for patients previously treated with docetaxel containing regimen for late state disease
a difference between cabazitaxel is, that unlike docetaxel, it is a poor substrate for Pgp
Pgp is thought to contribute the the constitutive and acquired resistance of cancer cells to taxanes |
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Term
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Definition
4 major 16 membered macrolide antibiotics
highly active in producing cell arrest at G/M phase resulting in apoptosis
[image]
stabilize microtubules triggering apoptosis
effective against multiresistant tumor cells
the key functional groups in the compound are 1) epoxide 2) thiazole 3) ketone
these compounds are macrolides (16 membered lactone ring) |
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Term
| advantages of epothilones over taxols |
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Definition
higher potency in some cases
active against some taxol resistant cell lines
higher aqueous solubility
simpler structures
[image]
epothilones have greater water solubility compared to taxol
the lactone ring can be opened up by hydrolysis to yield an inactive compound
the epoxide group is not essential for activity
a methyl group at position 12 leads to an increase in activity |
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Term
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Definition
[image]
semi synthetic analog of epothilone B
metabolically more stable than epothilone B
low susceptibility to multi drug resistance protein mediated efflux
balance needed to maintain therapeutic concentration in tumor cells, but to minimize GI toxicity
low plasma protein binding
increased water solubility
the presence of a lactam group instead of lactone renders the compound more metabolically stable
increased water solubility due to both H bond donors and acceptors present
t1/2 52 hours
CYP3A4 inhibitors can decrease metabolism and may increase risk of toxicity
metabolic stability of ixabepilone:
[image]
by inserting the lactam it is more stable to hydrolysis than the lactones
ixabepilone leads to microtubulin stabilization leading to G2/M arrest and induction of apoptosis
[image]
ixabepilone binds to beta tubulin contained in microtubules
the microtubules are stabilized leading to apoptosis |
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Term
| binding of taxol and epothilone B to beta-tubulin |
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Definition
taxol and the epothilones do not share a common pharmacophore
His 227 on beta tubulin plays an important role in binding the compound to the active site
taxol does not bind in an identical fashion
also, Arg 276 and Thr 274 form H bonds with the carbonyl groups of ixabepilone
a key interaction in taxol is the interaction of the oxetane ring with Thr 274
overall, epothilone B occupies a much smaller binding cavity compared to taxol
epothilone: thiazole ring is important for activity - interaction of H bonding with histadine - important for binding beta tubule |
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