Antifolate

Short description: Class of antimetabolite medications

Dihydrofolate reductase (DHFR)

Folic acid

|

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9).[1] Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).[2]

## Contents

* 1 Comparison of available agents
* 2 Mechanism
* 3 Limitations
* 3.1 Side-effects
* 3.2 Resistance
* 4 Drugs that incidentally antagonize folate
* 5 See also
* 6 References
* 7 External links

## Comparison of available agents

* Methotrexate

* Pemetrexed

* Raltitrexed

* Pralatrexate

Drug | Class | Pharmacologic target | Myelosuppressive effect | US pregnancy category | Indications | Notable adverse effects

|
|
|
|
|
|

Methotrexate[3] | Antineoplastic & immunosuppressant | Mammalian DHFR | +++ | X | Malignancies (esp. haematologic malignancies and osteosarcoma), ectopic pregnancy and autoimmune conditions (esp. rheumatoid arthritis, psoriasis, Granulomatosis with polyangiitis, Goodpasture syndrome, etc.) | Kidney or liver failure, Stevens–Johnson syndrome, toxic epidermal necrolysis, infection, aplastic anaemia, opportunistic infections and GI effects.
Pemetrexed[4] | Antineoplastic | Mammalian DHFR, TS, GARFT | +++ | D | Non-small cell lung carcinoma & mesothelioma | Nausea, vomiting, dyspnoea, constipation, chest pain, diarrhoea, weight loss, stomatitis, rash, fever, peripheral neuropathy, dehydration, kidney failure, Stevens–Johnson syndrome, toxic epidermal necrolysis and erythema multiforme.
Proguanil[5] | Antimalarial | Protozoal DHFR | +/- | C | Malaria, prevention and treatment | Abdominal pain, headaches, increased LFTs, myalgia, nausea, opportunistic infections, diarrhoea, vomiting, etc. Less commonly Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, liver failure, anaphylaxis, etc.
Pyrimethamine[6] | Antiprotozoal | Protozoal DHFR | +/- | C | Malaria, toxoplasmosis and pneumocystis jiroveci pneumonia. | Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis and aplastic anaemia.
Trimethoprim[7] | Broad-spectrum antimicrobial | Microbial DHFR | +/- | C | Numerous (especially when in combination with the sulfonamide, sulfamethoxazole); treatment & prophylaxis for pneumocystis jiroveci pneumonia, malaria and toxoplasmosis. Treatment of melioidosis, shigellosis, listeria, urinary tract infections, acute infectious exacerbations of chronic bronchitis, infection prophylaxis in HIV-positive individuals, cyclospora protozoa, etc. | Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis and aplastic anaemia.

## Mechanism

Many are primarily DHFR inhibitors, but raltitrexed is an inhibitor of thymidylate synthase, and pemetrexed inhibits both and a third enzyme.

Antifolates act specifically during DNA and RNA synthesis, and thus are cytotoxic during the S-phase of the cell cycle. Thus, they have a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well as causing the side-effects listed.

## Limitations

### Side-effects

The antifolate action specifically targets the fast-dividing cells, and tend to have adverse effects on the bone marrow, skin, and hair. As folate is vital in the first trimester of pregnancy for healthy fetal development, the use of antifolates is strongly contraindicated in pregnancy and carries significant teratogenic risk.

Low doses of methotrexate can deplete folate stores and cause side-effects that are similar to folate deficiency. Both high-folate diets and supplemental folic acid may help reduce the toxic side-effects of low-dose methotrexate without decreasing its effectiveness.[8][9] Anyone taking low-dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement.

### Resistance

While the role of folate as a cancer treatment is well established, its long-term effectiveness is diminished by cellular response. In response to decreased tetrahydrofolate (THF), the cell begins to transcribe more DHF reductase, the enzyme that reduces DHF to THF. Because methotrexate is a competitive inhibitor of DHF reductase, increased concentrations of DHF reductase can overcome the drugs inhibition.

Many new drugs are under development to reduce antifolate drug resistance.[10][11]

## Drugs that incidentally antagonize folate

The name antifolate usually refers to drugs whose folate antagonism is intentional. In contrast, there are some other drugs, of several drug classes, that antagonize folate incidentally, as an adverse effect, whether mildly or heavily. This effect is often not noticeable except when it causes a neural tube defect in a fetus carried by a woman taking the medication. Such drugs include some anticonvulsants (valproic acid, carbamazepine, phenobarbital, phenytoin, and primidone) and trimethoprim. Lamotrigine is also an anticonvulsant with known (from in vitro testing) weak anti-folate effects.[12]

## See also

* Sulfonamides, a class of antimicrobials that work by inhibiting folate biosynthesis.

## References

1. ↑ "NCI: antifolate". http://www.cancer.gov/dictionary?cdrid=44814.
2. ↑ Ivan M. Kompis; Khalid Islam; Rudolf L. Then (2005). "DNA and RNA Synthesis: Antifolates". Chem. Rev. 105 (2): 593–620. doi:10.1021/cr0301144. PMID 15700958.
3. ↑ "Trexall, Rheumatrex (methotrexate) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/trexall-methotrexate-343201#showall.
4. ↑ "Alimta (pemetrexed) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. 10 January 2014. http://reference.medscape.com/drug/alimta-pemetrexed-342209#showall.
5. ↑ "Paludrine (proguanil) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/paludrine-proguanil-342692#showall.
6. ↑ "Daraprim (pyrimethamine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/daraprim-pyrimethamine-342668#showall.
7. ↑ "Primsol, Proloprim (trimethoprim) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/primsol-proloprim-trimethoprim-342571#showall.
8. ↑ "Methotrexate in rheumatoid arthritis: folate supplementation should always be given". BioDrugs 8 (1): 164–75. 1997. doi:10.2165/00063030-199708030-00002. PMID 18020507.
9. ↑ "Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during long-term, low-dose methotrexate therapy for rheumatoid arthritis: Implications for cardiovascular disease prevention". Journal of Rheumatology 25 (3): 441–6. 1998. PMID 9517760.
10. ↑ Takimoto CH (1996). "New Antifolates: Pharmacology and Clinical Applications". Oncologist 1 (1 & 2): 68–81. doi:10.1634/theoncologist.1-1-68. PMID 10387971. http://theoncologist.alphamedpress.org/cgi/pmidlookup?view=long&pmid=10387971.
11. ↑ "Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I". Anti-Cancer Agents Med Chem 7 (5): 524–42. September 2007. doi:10.2174/187152007781668724. PMID 17896913. http://www.bentham-direct.org/pages/content.php?ACAMC/2007/00000007/00000005/0005W.SGM.
12. ↑ Brunton, Laurence (2011). Goodman & Gilman's pharmacological basis of therapeutics. (12th ed.). New York: McGraw-Hill. ISBN 978-0-07-162442-8.

## External links

* Antifolates at the US National Library of Medicine Medical Subject Headings (MeSH)

* v
* t
* e

Antibacterials: nucleic acid inhibitors (J01E, J01M)

Antifolates
(inhibits
purine metabolism,
thereby inhibiting
DNA and RNA synthesis)|

| DHFR inhibitor|

* 2,4-Diaminopyrimidine
* Trimethoprim#
* Brodimoprim
* Tetroxoprim
* Iclaprim†

|

Sulfonamides
(DHPS inhibitor)|

| Short-
acting|

* Sulfaisodimidine
* Sulfamethizole
* Sulfadimidine
* Sulfapyridine
* Sulfafurazole
* Sulfanilamide
* Prontosil
* Sulfathiazole
* Sulfathiourea

|

Intermediate-
acting|

* Sulfamethoxazole
* Sulfadiazine#
* Sulfamoxole

Long-
acting|

* Sulfadimethoxine
* Sulfadoxine
* Sulfalene
* Sulfametomidine
* Sulfametoxydiazine
* Sulfamethoxypyridazine
* Sulfaperin
* Sulfamerazine
* Sulfaphenazole
* Sulfamazone

Other/ungrouped|

* Sulfacetamide
* Sulfadicramide
* Sulfametrole
* Sulfanitran

Combinations|

* Trimethoprim/sulfamethoxazole#
* Ormetoprim/sulfadimethoxine

Other DHPS inhibitors|

* Dapsone

Topoisomerase
inhibitors/
quinolones/
(inhibits
DNA replication)|

| 1st g.|

* Cinoxacin‡
* Flumequine‡
* Nalidixic acid‡
* Oxolinic acid‡
* Pipemidic acid‡
* Piromidic acid‡
* Rosoxacin‡

|

Fluoro-
quinolones|

| 2nd g.|

* Ciprofloxacin#
* Ofloxacin
* Enoxacin‡
* Fleroxacin‡
* Lomefloxacin‡
* Nadifloxacin‡
* Norfloxacin‡
* Pefloxacin‡
* Rufloxacin‡

|

3rd g.|

* Levofloxacin#
* Balofloxacin‡
* Grepafloxacin‡
* Pazufloxacin‡
* Sparfloxacin‡
* Temafloxacin‡
* Tosufloxacin‡

4th g.|

* Besifloxacin
* Delafloxacin
* Gatifloxacin
* Finafloxacin
* Gemifloxacin
* Moxifloxacin#
* Clinafloxacin†
* Garenoxacin‡
* Prulifloxacin‡
* Sitafloxacin‡
* Trovafloxacin‡/Alatrofloxacin‡

Vet.|

* Danofloxacin
* Difloxacin
* Enrofloxacin
* Ibafloxacin
* Marbofloxacin
* Orbifloxacin
* Pradofloxacin
* Sarafloxacin‡

Newer non-fluorinated|

* Nemonoxacin

Related (DG)|

* Aminocoumarins: Novobiocin

Anaerobic DNA
inhibitors|

| Nitro- imidazole derivatives|

* Metronidazole#
* Tinidazole
* Ornidazole

|

Nitrofuran derivatives|

* Nitrofurantoin#
* Furazolidone‡
* Nifurtoinol

RNA synthesis|

| Rifamycins/
RNA polymerase|

* Rifampicin#
* Rifabutin#
* Rifapentine#
* Rifaximin
* Rifalazil§

|

Lipiarmycins|

* Fidaxomicin

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

* v
* t
* e

Intracellular chemotherapeutic agents / antineoplastic agents (L01)

SPs/MIs
(M phase)|

| Block microtubule assembly|

* Vinca alkaloids (Vinblastine#
* Vincristine#
* Vinflunine§
* Vindesine
* Vinorelbine#)

|

Block microtubule disassembly|

* Taxanes (Cabazitaxel
* Docetaxel#
* Larotaxel
* Ortataxel†
* Paclitaxel#
* Tesetaxel)
* Epothilones (Ixabepilone)

DNA replication
inhibitor|

| DNA precursors/
antimetabolites
(S phase)|

| Folic acid|

* Dihydrofolate reductase inhibitor (Aminopterin
* Methotrexate#
* Pemetrexed
* Pralatrexate)
* Thymidylate synthase inhibitor (Raltitrexed
* Pemetrexed)

|

Purine|

* Adenosine deaminase inhibitor (Pentostatin)

* Halogenated/ribonucleotide reductase inhibitors (Cladribine
* Clofarabine
* Fludarabine)
* Nelarabine

* Thiopurine (Tioguanine#
* Mercaptopurine#)

Pyrimidine|

* Thymidylate synthase inhibitor (Fluorouracil#
* Capecitabine#
* Doxifluridine
* Tegafur (+gimeracil/oteracil)
* Carmofur
* Floxuridine)

* DNA polymerase inhibitor (Cytarabine#)

* Ribonucleotide reductase inhibitor (Gemcitabine#)

* Hypomethylating agent (Azacitidine
* Decitabine)

Deoxyribonucleotide|

* Ribonucleotide reductase inhibitor (Hydroxycarbamide#)

Topoisomerase inhibitors
(S phase)|

| I|

* Camptotheca (Camptothecin
* Cositecan†
* Belotecan
* Gimatecan
* Exatecan
* Irinotecan#
* Lurtotecan‡
* Silatecan§
* Topotecan
* Rubitecan‡)

|

II|

* Podophyllum (Etoposide#
* Teniposide)

II+Intercalation|

* Anthracyclines (Aclarubicin
* Daunorubicin#
* Doxorubicin#
* Epirubicin
* Idarubicin
* Amrubicin†
* Pirarubicin
* Valrubicin
* Zorubicin)
* Anthracenediones (Mitoxantrone
* Pixantrone)

Crosslinking of DNA
(CCNS)|

| Alkylating|

* Nitrogen mustards: Chlormethine
* Cyclophosphamide# (Ifosfamide#
* Trofosfamide)
* Chlorambucil# (Melphalan
* Prednimustine)
* Bendamustine#
* Uramustine

* Nitrosoureas: Carmustine
* Lomustine (Semustine)
* Fotemustine
* Nimustine
* Ranimustine
* Streptozocin

* Alkyl sulfonates: Busulfan (Mannosulfan
* Treosulfan)

* Aziridines: Carboquone
* Thiotepa
* Triaziquone
* Triethylenemelamine

|

Platinum-based|

* Carboplatin#
* Cisplatin#
* Dicycloplatin
* Nedaplatin
* Oxaliplatin#
* Satraplatin

Nonclassical|

* Hydrazines (Procarbazine#)
* Triazenes (Dacarbazine#
* Temozolomide)
* Altretamine
* Mitobronitol
* Pipobroman

Intercalation|

* Streptomyces (Actinomycin#
* Bleomycin#
* Mitomycins
* Plicamycin)

Photosensitizers/PDT|

* Aminolevulinic acid / Methyl aminolevulinate
* Efaproxiral
* Porphyrin derivatives (Porfimer sodium
* Talaporfin
* Temoporfin
* Verteporfin)

Other|

| Enzyme inhibitors|

* FI (Tipifarnib§)
* CDK inhibitors (Abemaciclib
* Alvocidib†
* Palbociclib
* Ribociclib
* Seliciclib†)
* PrI
* Bortezomib
* Carfilzomib
* Ixazomib
* PhI (Anagrelide)
* IMPDI (Tiazofurin§)
* LI (Masoprocol)
* PARP inhibitor (Niraparib
* Olaparib
* Rucaparib)
* HDAC (Belinostat
* Panobinostat
* Romidepsin
* Vorinostat)
* PIKI (Idelalisib)

|

Receptor antagonists|

* ERA (Atrasentan)
* Retinoid X receptor (Bexarotene)
* Sex steroid (Testolactone)

Other/ungrouped|

* Amsacrine
* Trabectedin
* Retinoids (Alitretinoin
* Tretinoin#)
* Arsenic trioxide
* Asparagine depleters (Asparaginase#/Pegaspargase)
* Celecoxib
* Demecolcine
* Elesclomol§
* Elsamitrucin
* Estramustine phosphate
* Etoglucid
* Lonidamine
* Lucanthone
* Mitoguazone
* Mitotane
* Oblimersen†
* Omacetaxine mepesuccinate
* Eribulin

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

* v
* t
* e

Antiparasitics – antiprotozoal agents – Chromalveolate antiparasitics (P01)

Alveo-
late|

| Apicom-
plexa|

| Conoidasida/
(Coccidiostats)|

| Cryptosporidiosis|

* thiazolides (nitazoxanide)

|

Isosporiasis|

* trimethoprim/sulfamethoxazole#

Toxoplasmosis|

* pyrimethamine
* sulfadiazine
* clindamycin
* atovaquone

Aconoidasida|

| Malaria|

| Individual
agents|

| Hemozoin
inhibitors|

| Aminoquinolines|

* (4-): amodiaquine#
* chloroquine#
* hydroxychloroquine#

* (8-): primaquine#
* pamaquine‡
* tafenoquine†

|

4-Methanolquinolines|

* mefloquine#
* quinine#
* quinidine

Other|

* lumefantrine
* \+ artemether#

* halofantrine

Antifolates|

| DHFR inhibitors|

* pyrimethamine

* biguanides
* chlorproguanil
* proguanil#

|

Sulfonamides|

* sulfadoxine
* sulfalene

Co-formulation|

* sulfadoxine/pyrimethamine (SP)#

Sesquiterpene
lactones|

* artemether#
* artemisinin
* artemotil
* artesunate#
* dihydroartemisinin

Other|

* atovaquone (\+ proguanil)
* tetracycline
* doxycycline#
* clindamycin
* mepacrine
* pyronaridine
* piperaquine

Combi-
nations|

| Fixed-dose (co-formulated) ACTs|

* artemether/lumefantrine#
* arterolane/piperaquine
* artesunate/amodiaquine (ASAQ)
* artesunate/mefloquine (ASMQ)
* artesunate/pyronaridine
* dihydroartemisinin/piperaquine

|

Other combinations
(not co-formulated)|

* artesunate/mefloquine
* artesunate/SP
* quinine/clindamycin
* quinine/doxycycline
* quinine/tetracycline

Babesiosis|

* clindamycin

Cilio-
phora|

* Balantidiasis: tetracycline

Hetero-
kont|

* Blastocystosis: metronidazole

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

* v
* t
* e

Purine receptor modulators

Receptor
(ligands)|

| P0 (adenine)|

* Agonists: 8-Aminoadenine
* Adenine

|

(adenosine)|

* Agonists: 2-(1-Hexynyl)-N-methyladenosine
* 2-Cl-IB-MECA
* 2'-MeCCPA
* 4'-O-β-D-Glucosyl-9-O-(6''-deoxysaccharosyl)olivil
* 5'-N-ethylcarboxamidoadenosine
* Adenosine
* ADP
* AMP
* Apadenoson
* ATL-146e
* ATP
* BAY 60–6583
* Binodenoson
* Capadenoson
* CCPA
* CGS-21680
* CP-532,903
* Evodenoson
* GR 79236
* LUF-5835
* LUF-5845
* N6-Cyclopentyladenosine
* Namodenoson
* Neladenoson dalanate
* Piclidenoson
* Regadenoson
* SDZ WAG 994
* Selodenoson
* Sonedenoson
* Tecadenoson
* UK-432,097

* Antagonists: 8-Chlorotheophylline
* 8-Phenyl-1,3-dipropylxanthine
* 8-Phenyltheophylline
* Acefylline
* Aminophylline
* ATL-444
* Bamifylline
* Cafedrine
* Caffeine
* Caffeine citrate
* Cartazolate
* CGH-2466
* CGS-15943
* Choline theophyllinate
* Ciforadenant
* CPX
* CVT-6883
* Dimethazan
* DMPX
* DPCPX
* Dyphylline
* Enprofylline
* Etazolate
* Fenethylline
* IBMX
* Isovaleric acid
* Istradefylline
* KF-26777
* MRE3008F20
* MRS-1220
* MRS-1334
* MRS-1706
* MRS-1754
* MRS-3777
* Paraxanthine
* Pentoxifylline
* Preladenant
* Propentofylline
* Proxyphylline
* PSB-10
* PSB-11
* PSB-36
* PSB-603
* PSB-788
* PSB-1115
* Reversine
* Rolofylline
* SCH-442,416
* SCH-58261
* Theacrine
* Theobromine
* Theodrenaline
* Theophylline
* Tozadenant
* Tracazolate
* VUF-5574
* ZM-241,385

(nucleotide)|

| P2X
(ATP)|

* Agonists: 2-Me-SATP
* α,β-Me-ATP
* Adenosine
* ADP
* AMP
* Ap4A
* Ap5A
* ATP
* ATPγS
* BzATP
* Cibacron blue
* CTP
* D-β,γ-Me-ATP
* GTP
* HT-AMP
* Ivermectin
* L-β,γ-Me-ATP
* MRS-2219
* PAPET-ATP
* UTP
* Zinc

* Antagonists: 5-BDBD
* A-317491
* A-438079
* A-740003
* A-804598
* A-839977
* AF-353
* AZ-10606120
* AZ-11645373
* BBG
* Calcium
* Calmidazolium
* Chelerythrine
* Copper
* Emodin (Rheum officinale)
* Evans Blue
* Gefapixant
* GW-791343
* HMA
* Ip5I
* isoPPADS
* JNJ-47965567
* KN-04
* KN-62
* Magnesium
* MRS-2159
* NF-023
* NF-110
* NF-157
* NF-279
* NF-449
* Opiranserin (VVZ-149)
* Oxidized-ATP
* Phenol Red
* Phenolphthalein
* PPADS
* PPNDS
* PSB-12062
* Puerarin (Radix puerariae)
* Purotoxin 1
* RB-2
* Ro 0437626
* Ro 51
* RO-3
* Sodium ferulate (Angelica sinensis, Ligusticum wallichii)
* Suramin
* TC-P 262
* Tetramethylpyrazine (ligustrazine) (Ligusticum wallichii)
* TNP-ATP
* Zinc

|

P2Y|

* Agonists: 2-Me-SADP
* 2-Me-SATP
* 2-Thio-UTP
* 5-Br-UDP
* 5-OMe-UDP
* α,β-Me-ATP
* Adenosine
* ADP
* ADPβS
* Ap3A
* AR-C 67085MX
* ATP
* ATPγS
* CTP
* dATP
* Denufosol
* Diquafosol
* IDP
* ITP
* INS-365
* INS-37217
* MRS-2365
* MRS-2690
* MRS-2693
* MRS-2768
* MRS-2957
* MRS-4062
* NF-546
* PAPET-ATP
* PSB-0474
* PSB-1114
* UDP
* UDPβS
* UDP-galactose
* UDP-glucose
* UDP-N-acetylglucosamine
* Up3U
* UTP
* UTPγS

* Antagonists: 2-Me-SAMP
* A3P5PS
* AMPαS
* Ap4A
* AR-C 66096
* AR-C 67085MX
* AR-C 69931MX
* AR-C 118925XX
* ATP
* BzATP
* C1330-7
* Cangrelor
* Clopidogrel
* Elinogrel
* Ip5I
* MRS-2179
* MRS-2211
* MRS-2279
* MRS-2395
* MRS-2500
* MRS-2578
* NF-157
* NF-340
* PIT
* PPADS
* Prasugrel
* PSB-0739
* RB-2
* Regrelor
* Suramin
* Ticagrelor
* Ticlopidine
* UDP

Transporter
(blockers)|

| CNTs|

* 6-Hydroxy-7-methoxyflavone
* Adenosine
* dMeThPmR
* Estradiol
* KGO-2142
* KGO-2173
* MeThPmR
* Phloridzin
* Progesterone

|

ENTs|

* Barbiturates
* Benzodiazepines
* Cilostazol
* Dilazep
* Dipyridamole
* Estradiol
* Ethanol
* Hexobendine
* NBMPR
* Pentoxifylline
* Progesterone
* Propentofylline

PMAT|

* Decynium-22

Enzyme
(inhibitors)|

| XO|

* Allopurinol
* Amflutizole
* Benzbromarone
* Caffeic acid
* Cinnamaldehyde
* Cinnamomum osmophloeum
* Febuxostat
* Myo-inositol
* Kaempferol
* Myricetin
* Niraxostat
* Oxipurinol
* Phytic acid
* Pistacia integerrima
* Propolis
* Quercetin
* Tisopurine
* Topiroxostat

|

Others|

* Aminopterin
* Azathioprine
* Methotrexate
* Mycophenolic acid
* Pemetrexed
* Pralatrexate
* Many others

Others|

* Precursors: Adenine
* Adenosine
* AMP
* ADP
* ATP
* Cytosine
* Cytidine
* CMP
* CDP
* CTP
* Guanine
* Guanosine
* GMP
* GDP
* GTP
* Hypoxanthine
* Inosine
* IMP
* IDP
* ITP
* Ribose
* Uracil
* Uridine
* UMP
* UDP
* UTP

* Others: Chrysophanol (rhubarb)

See also: Receptor/signaling modulators

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*[v]: View this template
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*[ATP]: Adenosine triphosphate
*[CNTs]: Concentrative nucleoside transporters
*[ENTs]: Equilibrative nucleoside transporters
*[PMAT]: Plasma membrane monoamine transporter
*[XO]: Xanthine oxidase